Disubstituted alkyl-8-azabicyclo[3.2.1]octane compounds as mu opioid receptor antagonists

ABSTRACT

The invention provides novel 8-azabicyclo[3.2.1]octane compounds of formula (I): 
                         
where the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are antagonists at the mu opioid receptor. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat conditions associated with mu opioid receptor activity, and processes and intermediates useful for preparing such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No.12/229,636, filed Aug. 26, 2008, now U.S. Pat. No. 7,947,710 B2; whichclaims the benefit of U.S. Provisional Application No. 60/966,281, filedon Aug. 27, 2007, the disclosures of which are incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is directed to 8-azabicyclo[3.2.1]octane compounds whichare useful as mu opioid receptor antagonists. The invention is alsodirected to pharmaceutical compositions comprising such compounds,methods of using such compounds for treating or ameliorating medicalconditions mediated by mu opioid receptor activity, and processes andintermediates useful for preparing such compounds.

2. State of the Art

It is now generally understood that endogenous opioids play a complexrole in gastrointestinal physiology. Opioid receptors are expressedthroughout the body, both in the central nervous system and inperipheral regions including the gastrointestinal (GI) tract.

Compounds which function as agonists at opioid receptors, of whichmorphine is a prototypical example, are the mainstays of analgesictherapy for the treatment of moderate to severe pain. Unfortunately, useof opioid analgesics is often associated with adverse effects on the GItract, collectively termed opioid-induced bowel dysfunction (OBD). OBDincludes symptoms such as constipation, decreased gastric emptying,abdominal pain and discomfort, bloating, nausea, and gastroesophagealreflux. Both central and peripheral opioid receptors are likely involvedin the slowdown of gastrointestinal transit after opioid use. However,evidence suggests that peripheral opioid receptors in the GI tract areprimarily responsible for the adverse effects of opioids on GI function.

Since the side effects of opioids are predominantly mediated byperipheral receptors, whereas the analgesia is central in origin, aperipherally selective antagonist can potentially block undesirableGI-related side effects without interfering with the beneficial centraleffects of analgesia or precipitating central nervous system withdrawalsymptoms.

Of the three major opioid receptor subtypes, denoted mu, delta, andkappa, most clinically-used opioid analgesics are thought to act via muopioid receptor activation to exert analgesia and to alter GI motility.Accordingly, peripherally selective mu opioid antagonists are expectedto be useful for treating opioid-induced bowel dysfunction. Preferredagents will demonstrate significant binding to mu opioid receptors invitro and be active in vivo in GI animal models.

Postoperative ileus (POI) is a disorder of reduced motility of the GItract that occurs after abdominal or other surgery. The symptoms of POIare similar to those of OBD. Furthermore, since surgical patients areoften treated during and after surgery with opioid analgesics, theduration of POI may be compounded by the reduced GI motility associatedwith opioid use. Mu opioid antagonists useful for treating OBD aretherefore also expected to be beneficial in the treatment of POI.

SUMMARY OF THE INVENTION

The invention provides novel compounds that possess mu opioid receptorantagonist activity.

Accordingly, the invention provides a compound of formula (I):

-   -   wherein:    -   R¹ is —OR^(a) or —C(O)NR^(b)R^(c);    -   R² is selected from —NR^(a)C(O)R³, —NR^(a)C(O)NHR⁵,        —NR^(a)S(O)₂R⁷, and —C(O)NR^(f)R⁸;    -   R³ is selected from C₁₋₆ alkyl optionally substituted with one        or two substituents selected from R⁴, C₅₋₆cycloalkyl, and phenyl        optionally substituted with —S(O)₂NR^(b)R^(c);    -   R⁴ is selected from —OR^(d), —C(O)NR^(b)R^(c), —NR^(b)R^(c),        —C(O)OR^(d), —OC(O)R^(d), —S(O)₂R^(e), phenyl, and        C₅₋₆cycloalkyl;    -   R⁵ is C₁₋₆ alkyl optionally substituted with one or two        substituents selected from C₅₋₆cycloalkyl and phenyl optionally        substituted with halo, or —S(O)₂R⁶;    -   R⁶ is C₁₋₆alkyl or phenyl;    -   R⁷ is C₁₋₆ alkyl optionally substituted with —S(O)₂R^(e) or        phenyl optionally substituted with C₁₋₃alkyl;    -   R⁸ is C₁₋₆ alkyl optionally substituted with one or two        substituents selected from R⁴, indolyl, and imidazolyl, or        phenyl substituted with —S(O)₂NR^(b)R^(c);    -   R^(a), R^(b), R^(c), R^(d), and R^(f) are each independently        hydrogen or C₁₋₃alkyl;    -   R^(e) is C₁₋₃alkyl;    -   m is 0, 1, or 2;    -   n is 0, 1, or 2;    -   R⁹ and R¹⁰ are each hydrogen, or R⁹ and R¹⁰ taken together form        —CH₂—, provided that when R² is —C(O)NR^(f)R⁸, or when n is 0,        R⁹ and R¹⁰ are each hydrogen; and    -   the dashed lines represent optional bonds;    -   or a pharmaceutically-acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising acompound of the invention and a pharmaceutically-acceptable carrier.

The invention also provides a method of treating a disease or conditionameliorated by treatment with a mu opioid receptor antagonist, e.g. adisorder of reduced motility of the gastrointestinal tract such asopioid-induced bowel dysfunction and post-operative ileus, the methodcomprising administering to the mammal, a therapeutically effectiveamount of a compound or of a pharmaceutical composition of theinvention.

The compounds of the invention can also be used as research tools, i.e.to study biological systems or samples, or for studying the activity ofother chemical compounds. Accordingly, in another of its method aspects,the invention provides a method of using a compound of formula (I), or apharmaceutically acceptable salt thereof, as a research tool forstudying a biological system or sample or for discovering new compoundshaving mu opioid receptor activity, the method comprising contacting abiological system or sample with a compound of the invention anddetermining the effects caused by the compound on the biological systemor sample.

In separate and distinct aspects, the invention also provides syntheticprocesses and intermediates described herein, which are useful forpreparing compounds of the invention.

The invention also provides a compound of the invention as describedherein for use in medical therapy, as well as the use of a compound ofthe invention in the manufacture of a formulation or medicament fortreating a disease or condition ameliorated by treatment with a muopioid receptor antagonist, e.g. a disorder of reduced motility of thegastrointestinal tract, in a mammal.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides 8-azabicyclo[3.2.1]octane mu opioid receptorantagonists of formula (I), or pharmaceutically-acceptable saltsthereof. The following substituents and values are intended to providerepresentative examples of various aspects of this invention. Theserepresentative values are intended to further define such aspects andare not intended to exclude other values or limit the scope of theinvention.

In a specific aspect of the invention, R¹ is —OR^(a) or—C(O)NR^(b)R^(c).

In another specific aspect, R¹ is —OH or —C(O)NH₂.

In yet another specific aspect, R¹ is —C(O)NH₂.

In a specific aspect, R² is selected from —NR^(a)C(O)R³,—NR^(a)C(O)NHR⁵, —NR^(a)S(O)₂R⁷, and —C(O)NR^(a)R⁸.

In another specific aspect, R² is —NR^(a)C(O)R³ wherein R³ is selectedfrom C₁₋₆alkyl optionally substituted with one or two substituentsselected from R⁴, C₅₋₆cycloalkyl, and phenyl optionally substituted with—S(O)₂NR^(b)R^(c).

In another specific aspect, R² is —NR^(a)C(O)R³ wherein R^(a) ishydrogen or methyl; and R³ is selected from C₁₋₄ alkyl optionallysubstituted with one substituent selected from —OH, —C(O)NH₂, —NH₂,—N(CH₃)₂, —C(O)OH, —OC(O)CH₃, —S(O)₂CH₃, and cyclohexyl, cyclohexyl, andphenyl optionally substituted with —S(O)₂NH₂.

In yet another specific aspect, R² is —NHC(O)CH₂OH or —N(CH₃)C(O)CH₂OH.

In a specific aspect, R² is —NR^(a)C(O)NHR⁵ wherein R⁵ is selected fromC₁₋₆ alkyl optionally substituted with one or two substituents selectedfrom C₅₋₆cycloalkyl and phenyl optionally substituted with halo, or—S(O)₂R⁶.

In another specific aspect, R² is —NR^(a)C(O)NHR⁵ wherein R^(a) ishydrogen or methyl; and R⁵ is C₁₋₄ alkyl optionally substituted with onesubstituent selected from cyclohexyl, phenyl, and 4-fluorophenyl, or—S(O)₂-phenyl.

In yet another specific aspect, R² is —NHC(O)NHCH₂-cyclohexyl.

In a specific aspect, R² is —NR^(a)S(O)₂R⁷ wherein R⁷ is C₁₋₆alkyloptionally substituted with —S(O)₂R^(e) or phenyl optionally substitutedwith C₁₋₃alkyl.

In another specific aspect R² is —NR^(a)S(O)₂R⁷ wherein R^(a) ishydrogen or methyl; and R⁷ is C₁₋₄ alkyl optionally substituted with—S(O)₂CH₃, or phenyl optionally substituted with methyl.

In yet another specific aspect R² is —NHS(O)₂CH₃ or —NHS(O)₂CH₂S(O)₂CH₃.

In a specific aspect, R² is —C(O)NR^(f)R⁸ wherein R⁸ is C₁₋₆ alkyloptionally substituted with one or two substituents selected from R⁴,indolyl, and imidazolyl, or phenyl substituted with —S(O)₂NR^(b)R^(c).

In another specific aspect, R² is —C(O)NR^(f)R⁸ wherein R^(f) ishydrogen or methyl, and R⁸ is C₁₋₆ alkyl optionally substituted with oneor two substituents selected from —OH, —C(O)NH₂, —NH₂, indolyl, andimidazolyl, or 4-S(O)₂NH₂-phenyl.

In yet another specific aspect, R² is —C(O)NH(CH₂)₂N(CH₃)₂.

In a specific aspect, R⁹ and R¹⁰ are each hydrogen.

In another specific aspect, R⁹ and R¹⁰ taken together form —CH₂— and nis 1.

In a specific aspect, R^(a), R^(b), R^(c), R^(d), and R^(e) are eachindependently hydrogen or C₁₋₃alkyl.

In another specific aspect, R^(a), R^(b), R^(c), R^(d), and R^(e) areeach independently hydrogen or methyl.

In another specific aspect, R^(a), R^(b), R^(c), R^(d), and R^(f) areeach hydrogen.

In a specific aspect, R^(e) is C₁₋₃alkyl.

In another specific aspect, R^(e) is methyl.

In a specific aspect, m is 0, 1, or 2.

In another specific aspect, m is 1.

In a specific aspect, n is 0, 1, or 2.

In another specific aspect, n is 1 or 2.

In specific aspects, m is 0 and n is 1; or m is 1 and n is 0.

In a specific aspect, the optional bonds represented by dashed lines arepresent, i.e. the cyclic moiety in formula (I) bearing the substituentR⁹ is phenyl.

In another specific aspect, the optional bonds represented by dashedlines are absent, i.e. the cyclic moiety in formula (I) bearing thesubstituent R⁹ is cyclohexyl.

In a specific aspect, the invention provides a compound of formula (I)wherein:

-   -   R¹ is —OH or —C(O)NH₂;    -   R² is selected from —NR^(a)C(O)R³, —NR^(a)C(O)NHR⁵,        —NR^(a)S(O)₂R⁷, and —C(O)NR^(f)R⁸;    -   R³ is selected from C₁₋₄ alkyl optionally substituted with one        substituent selected from —OH, —C(O)NH₂, —NH₂, —N(CH₃)₂,        —C(O)OH, —OC(O)CH₃, —S(O)₂CH₃, and cyclohexyl, cyclohexyl, and        phenyl optionally substituted with —S(O)₂NH₂;    -   R⁵ is C₁₋₄ alkyl optionally substituted with one substituent        selected from cyclohexyl, phenyl, and 4-fluorophenyl, or        —S(O)₂-phenyl;    -   R⁷ is C₁₋₄ alkyl optionally substituted with —S(O)₂CH₃, or        phenyl optionally substituted with methyl;    -   R⁸ is C₁₋₆ alkyl optionally substituted with one or two        substituents selected from —OH, —C(O)NH₂, —NH₂, indolyl, and        imidazolyl, or 4-S(O)₂NH₂-phenyl;    -   R⁹ and R¹⁰ are each hydrogen;    -   R^(a) is hydrogen or methyl;    -   m is 0, 1, or 2;    -   n is 0, 1, or 2;    -   or a pharmaceutically-acceptable salt thereof.

The invention further provides the compounds of Examples 1-139 herein.

The chemical naming convention used herein is illustrated for thecompound of Example 1:

which is cyclohexanecarboxylic acid{1-cyclohexylmethyl-2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}amide.Alternatively, using the IUPAC conventions as implemented in AutoNomsoftware, (MDL Information Systems, GmbH, Frankfurt, Germany), thecompound is denoted cyclohexanecarboxylic acid{1-cyclohexylmethyl-2-[(1R,3R,5S)-3-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}amide.The names used herein therefore correspond to the IUPAC notation withthe endo orientation of the substituted phenyl group with respect to the8-azabicyclo[3.2.1]octane group indicated explicitly. All of thecompounds of the invention are in the endo orientation. For convenience,as used herein, the term “8-azabicycloctane” means8-azabicyclo[3.2.1]octane.

In addition to the endo stereochemistry with respect to the bicyclogroup, the compounds of the invention may contain a chiral center in thesubstituent R² and at the carbon atom bearing the substituent R².Accordingly, the invention includes racemic mixtures, purestereoisomers, and stereoisomer-enriched mixtures of such isomers,unless otherwise indicated. When the stereochemistry of a compound isspecified, including both the orientation with respect to the8-azabicyclooctane group and the chirality in a substituent R², or atthe carbon atom bearing the substituent R², it will be understood bythose skilled in the art, that minor amounts of other stereoisomers maybe present in the compositions of the invention unless otherwiseindicated, provided that any utility of the composition as a whole isnot eliminated by the presence of such other isomers.

DEFINITIONS

When describing the compounds, compositions and methods of theinvention, the following terms have the following meanings, unlessotherwise indicated.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched or combinations thereof. Unless otherwisedefined, such alkyl groups typically contain from 1 to 10 carbon atoms.Representative alkyl groups include, by way of example, methyl, ethyl,n-propyl (n-Pr), isopropyl (i-Pr), n-butyl (n-Bu), sec-butyl, isobutyl,tert-butyl, n-pentyl, n-hexyl, 2,2-dimethylpropyl, 2-methylbutyl,3-methylbutyl, 2-ethylbutyl, 2,2-dimethylpentyl, 2-propylpentyl, and thelike.

The term “cycloalkyl” means a monovalent saturated carbocyclic groupwhich may be monocyclic or multicyclic. Unless otherwise defined, suchcycloalkyl groups typically contain from 3 to 10 carbon atoms.Representative cycloalkyl groups include, by way of example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (chexyl), cycloheptyl,cyclooctyl, adamantyl, and the like.

The term “compound” means a compound that was synthetically prepared orprepared in any other way, such as by in vivo metabolism.

The term “therapeutically effective amount” means an amount sufficientto effect treatment when administered to a patient in need of treatment.

The term “treatment” as used herein means the treatment of a disease,disorder, or medical condition in a patient, such as a mammal(particularly a human) which includes:

-   -   (a) preventing the disease, disorder, or medical condition from        occurring, i.e., prophylactic treatment of a patient;    -   (b) ameliorating the disease, disorder, or medical condition,        i.e., eliminating or causing regression of the disease,        disorder, or medical condition in a patient, including        counteracting the effects of other therapeutic agents;    -   (c) suppressing the disease, disorder, or medical condition,        i.e., slowing or arresting the development of the disease,        disorder, or medical condition in a patient; or    -   (d) alleviating the symptoms of the disease, disorder, or        medical condition in a patient.

The term “pharmaceutically-acceptable salt” means a salt prepared froman acid or base which is acceptable for administration to a patient,such as a mammal. Such salts can be derived frompharmaceutically-acceptable inorganic or organic acids and frompharmaceutically-acceptable bases. Typically,pharmaceutically-acceptable salts of compounds of the present inventionare prepared from acids.

Salts derived from pharmaceutically-acceptable acids include, but arenot limited to, acetic, adipic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,glycolic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, oxalic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic(1-hydroxy-2-naphthoic acid), naphthalene-1,5-disulfonic acid and thelike.

The term “amino-protecting group” means a protecting group suitable forpreventing undesired reactions at an amino nitrogen. Representativeamino-protecting groups include, but are not limited to, formyl; acylgroups, for example alkanoyl groups, such as acetyl andtri-fluoroacetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl(Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl(Bn), trityl (Tr), and 1,1-di-(4′-methoxyphenyl)methyl; silyl groups,such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); andthe like.

General Synthetic Procedures

Compounds of the invention can be prepared from readily availablestarting materials using the following general methods and procedures.Although a particular aspect of the present invention is illustrated inthe schemes below, those skilled in the art will recognize that allaspects of the present invention can be prepared using the methodsdescribed herein or by using other methods, reagents and startingmaterials known to those skilled in the art. It will also be appreciatedthat where typical or preferred process conditions (i.e., reactiontemperatures, times, mole ratios of reactants, solvents, pressures,etc.) are given, other process conditions can also be used unlessotherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvent used, but such conditions can bedetermined by one skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group, as well assuitable conditions for protection and deprotection, are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and G. M. Wuts, ProtectingGroups in Organic Synthesis, Third Edition, Wiley, New York, 1999, andreferences cited therein.

In one method of synthesis, compounds of the invention in which R² takesthe value —NR^(a)C(O)R³, —NR^(a)C(O)NHR⁵, or —NR^(a)S(O)₂R⁷ are preparedas illustrated in Scheme A1. (The substituents and variables shown inthe following schemes have the definitions provided above unlessotherwise indicated).

In reaction (i) of Scheme A1, R^(3a) represents R³ or a protected formof R³, and L represents a leaving group, such as chloro, or R^(3a)C(O)-Lrepresents a carboxylic acid or a carboxylate salt. For example, toprepare a compound in which R³ is —CH₂OH, a useful reagent isacetoxyacetyl chloride, in which R^(3a) is —CH₂OC(O)CH₃ and L is chloro.When R^(3a) is a protected form of R³, the reaction also includes adeprotection step, which is not shown.

Optimal reaction conditions for reaction (i) of Scheme A1 may varydepending on the chemical properties of the reagent R^(3a)C(O)-L, as iswell known to those skilled in the art. For example, when L is a haloleaving group, such as chloro, the reaction is typically conducted bycontacting intermediate (II) with between about 1 and about 2equivalents of a compound of formula R^(3a)C(O)-L in an inert diluent,such as dichloromethane. Optionally, the reaction is conducted in thepresence of base, for example between about 1 and about 6 equivalents ofbase, such as N,N-diisopropylethylamine or triethylamine. Suitable inertdiluents also include 1,1,2,2-tetrachloroethane, tetrahydrofuran,dimethylacetamide, and the like. The reaction is typically conducted ata temperature in the range of about −50° C. to about 30° C. for about aquarter hour to about 16 hours, or until the reaction is substantiallycomplete.

When the reagent R^(3a)C(O)-L is a carboxylic acid or a carboxylatesalt, the reaction is typically conducted by contacting intermediate(II) with between about 1 and about 5 equivalents of the acidR^(3a)C(O)OH or the carboxylate salt, for example, R^(3a)C(O)OLi, in aninert diluent, optionally in the presence of an excess of base, both asdescribed above, and in the presence of between about 1 and about 6equivalents of an activating agent such as N,N-carbonyl diimidazole(CDI), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC). The reaction istypically conducted at a temperature in the range of about 25° C. toabout 100° C. for about 2 hours to about 16 hours, or until the reactionis substantially complete.

The preparation of urea compounds of formula (Ib) is illustrated inreaction (ii) of Scheme A1. The reaction is typically conducted bycontacting intermediate (II) with between about 1 and about 2equivalents of an isocyanate compound R⁵—N═C═O in the presence ofbetween about 3 and about 6 equivalents of base, such asN,N-diisopropylethylamine. The reaction is typically conducted atambient temperature for about an hour to about 16 hours, or until thereaction is substantially complete.

Reaction (iii) of Scheme A1 illustrates the preparation of sulfonamidecompounds of formula (Ic). The reaction is typically conducted bycontacting intermediate (II) with between about 1 and about 2equivalents of a sulfonyl compound R⁷S(O)₂L′, where L′ represents aleaving group such as chloro, for example, R⁷S(O)₂L′ is methanesulfonylchloride. The reaction is carried out under similar conditions to thosedescribed above for reaction (i) when L represents a halo leaving group.Optionally, the reaction includes between about 1 and about 2equivalents of a base such as 1,4-diazabicyclo[2.2.2]-octane (DABCO).

In another method of synthesis, compounds of the invention in which R²takes the value —C(O)NR^(f)R⁸, are prepared as illustrated in Scheme A2.

Typically, the reaction is conducted by contacting intermediate (IId)with between about 1 and about 2 equivalents of the amine HNR^(f)R⁸under the amide coupling conditions described above for reaction (i) ofScheme A where the reagent R^(3a)C(O)-L is a carboxylic acid.

General procedures for the preparation of an intermediate of formula(II) are illustrated in Scheme B1

where P¹ is an amino-protecting group.

In Scheme B1, an intermediate of formula (IV), is reductivelyN-alkylated by reaction with an aldehyde of formula (III) to provide aprotected intermediate (not shown) which is deprotected by conventionalmeans to provide intermediate (II). The reaction is typically conductedby contacting intermediate (IV) with between about 1 and about 2equivalents of aldehyde (III) in a suitable inert diluent, such asdichloromethane, in the presence of between about 0.9 and about 2equivalents of a reducing agent. The reaction is typically conducted ata temperature in the range of about 0° C. to ambient temperature forabout a half hour to about 3 hours or until the reaction issubstantially complete. Typical reducing agents include sodiumtriacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride.The product (II) is isolated by conventional means.

Alternatively, an intermediate (II) could be prepared by a similarprocess using the carboxylic acid corresponding to intermediate (III)under typical amide coupling conditions as described, for example, inPreparation 7, below.

An exemplary process for the preparation of an intermediate of formula(IId) is shown in Scheme B2.

where P² represents a C₁₋₃alkyl or a hydroxy-protecting group. Thereaction is typically conducted by contacting intermediate (IIId) withabout 1 equivalent of the bicyclooctane intermediate (IV) in an inertdiluent in the presence of an excess of base, for example between about3 and about 5 equivalents of base, such as N,N-diisopropylethylamine ortriethylamine. The reaction is typically conducted at a temperaturebetween about 25 and about 75° C. for between about 3 hours and about 16hours or until the reaction is substantially complete. An intermediateof formula (IId) in which R¹ is —C(O)NH₂ can be prepared from anintermediate (IId) in which R¹ is —OH through triflate and nitrileintermediates by a procedure analogous to that of Scheme D following andfurther described in the Examples below.

Aldehydes of formula (III) are commercially available or can be preparedby oxidation of the corresponding alcohol or by reduction of acorresponding ester by conventional procedures. Intermediates of formula(IIId) are also commercially available or are readily prepared fromcommercial starting materials as exemplified below.

Intermediates of formula (IV) can be prepared from readily availablestarting materials. For example, one process for the preparation ofintermediate (IV′) in which R¹ is hydroxy is illustrated in Scheme C.

where Bn denotes the amino-protecting group benzyl. Protected8-azabicyclo[3.2.1]octanone 1 is typically obtained from commercialsources and it can be prepared by the reaction of 2,5-dimethoxytetrahydrofuran with benzylamine and 1,3-acetonedicarboxylic acid in anacidic aqueous solution in the presence of a buffering agent asdescribed in US 2005/0228014. (See also, U.S. Pat. No. 5,753,673).

First, intermediate 1 is added to a solution of between about 1 andabout 2 equivalents of the Grignard reagent 3-methoxyphenyl magnesiumbromide in an inert diluent. The reaction is typically conducted at atemperature of between about 0° C. and about 10° C. for between about 1and about 3 hours or until the reaction is substantially complete.Transmetalation of the Grignard reagent from magnesium to cerium byreaction with an equivalent amount of cerous chloride prior to use isadvantageous for obtaining a good yield of intermediate 2. The hydroxysubstituent is eliminated from intermediate 2 by treatment with aqueous6N HCl to provide the hydrochloride salt of intermediate 3. Thisreaction is typically conducted at a temperature of between about 50° C.and about 100° C. for between about 1 and about 3 hours or until thereaction is substantially complete.

Hydrogenation of intermediate 3 saturates the double bond of the alkenemoiety and removes the benzyl protecting group to provide intermediate4. Typically, the reaction is conducted by exposing the HCl salt of 3dissolved in ethanol to a hydrogen atmosphere in the presence of atransition metal catalyst. Finally, the methyl group is removed fromintermediate 4 by contacting a cooled solution of intermediate 4 in aninert diluent with between about 1 and about 2 equivalents of borontribromide, hydrogen bromide, or boron trichloride. The reaction istypically conducted at a temperature of between about −80° C. and about0° C. for between about 12 and about 36 hours or until the reaction issubstantially complete. Intermediate (IV′) can be isolated byconventional procedures as a free base or as a hydrobromide salt.Crystallization of the hydrobromide salt provides intermediate (IV′)with high stereospecificity in the endo configuration (endo to exo ratioof greater than 99.1:0.8).

A process for preparing intermediate (IV″) in which the variable R¹ is—C(O)NH₂ uses the phenol intermediate (IV′) as a starting material asshown in Scheme D.

where —OTf represents trifluoromethane sulfonate (commonly triflate) andP² represents an amino-protecting group, such as Boc ortri-fluoroacetyl.

For example, when Boc is used as the protecting group, first, the phenolintermediate (IV′) is typically reacted with about 1 equivalent ofdi-tert-butyl dicarbonate (commonly Boc₂O) to provide the Boc-protectedintermediate 5. The reactants are typically cooled to about 0° C. andthen allowed to warm to ambient temperature over a period of betweenabout 12 and about 24 hours. When tri-fluoroacetyl is used as theprotecting group, typically (IV′) is reacted with about 2 equivalents oftri-fluoroacetyl anhydride to form the protected intermediate 5. Next,intermediate 5 in an inert diluent is contacted with a slight excess,for example about 1.1 equivalents of trifluoromethane sulfonyl chloridein the presence of between about 1 and about 2 equivalents of base toprovide intermediate 6 which can be isolated by conventional procedures.Reaction of 6 with zinc cyanide in the presence of a transition metalcatalyst, provides intermediate 7. This reaction is typically conductedat a temperature between about 60° C. and 120° C. under an inertatmosphere for about 2 to about 12 hours or until the reaction issubstantially complete.

Finally, the nitrile intermediate 7 is hydrolyzed and deprotected toprovide the carboxamide intermediate (IV″). Typically, in this reaction,when P² is Boc, intermediate 7 in an acidic solvent, for exampletrifluoroacetic acid, is contacted with between about 4 and about 6equivalents of concentrated sulfuric acid. Typically the reaction isconducted in the temperature range of between about 50° C. and about 80°C. for about 8 to about 24 hours or until the reaction is substantiallycomplete. The product is typically isolated in freebase form. When atri-fluoroacetyl protecting group is used, the nitrile intermediate isfirst hydrolyzed to the carboxamide in concentrated sulfuric acid asdescribed above. Quenching of the hydrolysis reaction by addition ofbase also removes the protecting group. The product is isolated as thefreebase or as the hydrochloric acid salt.

Further details regarding specific reaction conditions and otherprocedures for preparing representative compounds of the invention orintermediates thereto are described in the examples below.

Accordingly, in a method aspect, the invention provides a process forpreparing a compound of formula (I), or a salt thereof, the processcomprising (a) reacting a compound of formula (II) with a compound offormula R^(3a)C(O)-L, R⁵—N═C═O, or R⁷S(O)₂-L′ or (b) reacting a compoundof formula (IId) with a compound of formula HNR^(f)R⁸ to provide acompound of formula (I), or a salt thereof.

In an additional aspect, the invention provides a compound of formula(II) and a compound of formula (IId) wherein the variables R¹, R⁹, R¹⁰,n, and m take any of the values described in aspects of the inventiondisclosed above. In particular, the invention provides a compound offormula (II), wherein R¹ is —C(O)NH₂ and a compound of formula (IId)wherein R¹ is —C(O)NH₂.

Pharmaceutical Compositions

The 8-azabicyclooctane compounds of the invention are typicallyadministered to a patient in the form of a pharmaceutical composition orformulation. Such pharmaceutical compositions may be administered to thepatient by any acceptable route of administration including, but notlimited to, oral, rectal, vaginal, nasal, inhaled, topical (includingtransdermal) and parenteral modes of administration.

Accordingly, in one of its compositions aspects, the invention isdirected to a pharmaceutical composition comprising apharmaceutically-acceptable carrier or excipient and a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof. Optionally, such pharmaceutical compositionsmay contain other therapeutic and/or formulating agents if desired. Whendiscussing compositions, the “compound of the invention” may also bereferred to herein as the “active agent”. As used herein, the term“compound of the invention” is intended to include compounds of formula(I) as well as the species embodied in formulas (Ia), (Ib), (Ic), and(Id). “Compound of the invention” includes, in addition,pharmaceutically-acceptable salts and solvates of the compound unlessotherwise indicated.

The pharmaceutical compositions of the invention typically contain atherapeutically effective amount of a compound of the present inventionor a pharmaceutically-acceptable salt thereof. Typically, suchpharmaceutical compositions will contain from about 0.1 to about 95% byweight of the active agent; preferably, from about 5 to about 70% byweight; and more preferably from about 10 to about 60% by weight of theactive agent.

Any conventional carrier or excipient may be used in the pharmaceuticalcompositions of the invention. The choice of a particular carrier orexcipient, or combinations of carriers or excipients, will depend on themode of administration being used to treat a particular patient or typeof medical condition or disease state. In this regard, the preparationof a suitable pharmaceutical composition for a particular mode ofadministration is well within the scope of those skilled in thepharmaceutical arts. Additionally, the carriers or excipients used inthe pharmaceutical compositions of this invention arecommercially-available. By way of further illustration, conventionalformulation techniques are described in Remington: The Science andPractice of Pharmacy, 20^(th) Edition, Lippincott Williams & White,Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical DosageForms and Drug Delivery Systems, 7^(th) Edition, Lippincott Williams &White, Baltimore, Md. (1999).

Representative examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, the following:sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose, such as microcrystalline cellulose,and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients, such as cocoa butter and suppository waxes; oils, suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; glycols, such as propylene glycol; polyols,such as glycerin, sorbitol, mannitol and polyethylene glycol; esters,such as ethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; and other non-toxic compatible substances employed inpharmaceutical compositions.

Pharmaceutical compositions are typically prepared by thoroughly andintimately mixing or blending the active agent with apharmaceutically-acceptable carrier and one or more optionalingredients. The resulting uniformly blended mixture can then be shapedor loaded into tablets, capsules, pills and the like using conventionalprocedures and equipment.

The pharmaceutical compositions of the invention are preferably packagedin a unit dosage form. The term “unit dosage form” refers to aphysically discrete unit suitable for dosing a patient, i.e., each unitcontaining a predetermined quantity of active agent calculated toproduce the desired therapeutic effect either alone or in combinationwith one or more additional units. For example, such unit dosage formsmay be capsules, tablets, pills, and the like, or unit packages suitablefor parenteral administration.

In one embodiment, the pharmaceutical compositions of the invention aresuitable for oral administration. Suitable pharmaceutical compositionsfor oral administration may be in the form of capsules, tablets, pills,lozenges, cachets, dragees, powders, granules; or as a solution or asuspension in an aqueous or non-aqueous liquid; or as an oil-in-water orwater-in-oil liquid emulsion; or as an elixir or syrup; and the like;each containing a predetermined amount of a compound of the presentinvention as an active ingredient.

When intended for oral administration in a solid dosage form (i.e., ascapsules, tablets, pills and the like), the pharmaceutical compositionsof the invention will typically comprise the active agent and one ormore pharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate. Optionally or alternatively, such solid dosageforms may also comprise: fillers or extenders, such as starches,microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/orsilicic acid; binders, such as carboxymethylcellulose, alginates,gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, suchas glycerol; disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and/or sodium carbonate; solution retarding agents, such as paraffin;absorption accelerators, such as quaternary ammonium compounds; wettingagents, such as cetyl alcohol and/or glycerol monostearate; absorbents,such as kaolin and/or bentonite clay; lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, and/or mixtures thereof; coloring agents; and buffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants can also be presentin the pharmaceutical compositions of the invention. Examples ofpharmaceutically-acceptable antioxidants include: water-solubleantioxidants, such as ascorbic acid, cysteine hydrochloride, sodiumbisulfate, sodium metabisulfate, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate,alpha-tocopherol, and the like; and metal-chelating agents, such ascitric acid, ethylenediamine tetraacetic acid, sorbitol, tartaric acid,phosphoric acid, and the like. Coating agents for tablets, capsules,pills and like, include those used for enteric coatings, such ascellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid-methacrylic acid estercopolymers, cellulose acetate trimellitate, carboxymethyl ethylcellulose, hydroxypropyl methyl cellulose acetate succinate, and thelike.

Pharmaceutical compositions of the invention may also be formulated toprovide slow or controlled release of the active agent using, by way ofexample, hydroxypropyl methyl cellulose in varying proportions; or otherpolymer matrices, liposomes and/or microspheres. In addition, thepharmaceutical compositions of the invention may optionally containopacifying agents and may be formulated so that they release the activeingredient only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active agent can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Suitable liquid dosage forms for oral administration include, by way ofillustration, pharmaceutically-acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. Liquid dosage formstypically comprise the active agent and an inert diluent, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (esp., cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Suspensions, inaddition to the active ingredient, may contain suspending agents suchas, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

The compounds of this invention can also be administered parenterally(e.g. by intravenous, subcutaneous, intramuscular or intraperitonealinjection). For parenteral administration, the active agent is typicallyadmixed with a suitable vehicle for parenteral administration including,by way of example, sterile aqueous solutions, saline, low molecularweight alcohols such as propylene glycol, polyethylene glycol, vegetableoils, gelatin, fatty acid esters such as ethyl oleate, and the like.Parenteral formulations may also contain one or more anti-oxidants,solubilizers, stabilizers, preservatives, wetting agents, emulsifiers,buffering agents, or dispersing agents. These formulations may berendered sterile by use of a sterile injectable medium, a sterilizingagent, filtration, irradiation, or heat.

Alternatively, the pharmaceutical compositions of the invention areformulated for administration by inhalation. Suitable pharmaceuticalcompositions for administration by inhalation will typically be in theform of an aerosol or a powder. Such compositions are generallyadministered using well-known delivery devices, such as a metered-doseinhaler, a dry powder inhaler, a nebulizer or a similar delivery device.

When administered by inhalation using a pressurized container, thepharmaceutical compositions of the invention will typically comprise theactive ingredient and a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas.Additionally, the pharmaceutical composition may be in the form of acapsule or cartridge (made, for example, from gelatin) comprising acompound of the invention and a powder suitable for use in a powderinhaler. Suitable powder bases include, by way of example, lactose orstarch.

The compounds of the invention can also be administered transdermallyusing known transdermal delivery systems and excipients. For example,the active agent can be admixed with permeation enhancers, such aspropylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-onesand the like, and incorporated into a patch or similar delivery system.Additional excipients including gelling agents, emulsifiers and buffers,may be used in such transdermal compositions if desired.

If desired, the compounds of this invention may be administered incombination with one or more other therapeutic agents. In thisembodiment, a compound of this invention is either physically mixed withthe other therapeutic agent to form a composition containing bothagents; or each agent is present in separate and distinct compositionswhich are administered to the patient simultaneously or sequentially.

For example, a compound of formula I can be combined with secondtherapeutic agent using conventional procedures and equipment to form acomposition comprising a compound of formula I and a second therapeuticagent. Additionally, the therapeutic agents may be combined with apharmaceutically acceptable carrier to form a pharmaceutical compositioncomprising a compound of formula I, a second therapeutic agent and apharmaceutically acceptable carrier. In this embodiment, the componentsof the composition are typically mixed or blended to create a physicalmixture. The physical mixture is then administered in a therapeuticallyeffective amount using any of the routes described herein.Alternatively, the therapeutic agents may remain separate and distinctbefore administration to the patient. In this embodiment, the agents arenot physically mixed together before administration but are administeredsimultaneously or at separate times as separate compositions. Suchcompositions can be packaged separately or may be packaged together as akit. The two therapeutic agents in the kit may be administered by thesame route of administration or by different routes of administration.

Any therapeutic agent compatible with the compounds of the presentinvention may be used as the second therapeutic agent. In particular,prokinetic agents acting via mechanisms other than mu opioid receptorantagonism may be used in combination with the present compounds. Forexample, 5-HT₄ receptor agonists, such as tegaserod, renzapride,mosapride, prucalopride, 1-isopropyl-1H-indazole-3-carboxylic acid{(1S,3R,5R)-8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide,1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid{(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide,and4-(4-{[(2-isopropyl-1H-benzoimidazole-4-carbonyl)amino]methyl}-piperidin-1-ylmethyl)piperidine-1-carboxylicacid methyl ester and pharmaceutically-acceptable salts thereof may beused as the second therapeutic agent.

Additional useful prokinetic agents and other agents forgastrointestinal disorders include, but are not limited to, 5-HT₃receptor agonists (e.g. pumosetrag), 5-HT_(1A) receptor antagonists(e.g. AGI 001), alpha-2-delta ligands (e.g. PD-217014), chloride channelopeners (e.g. lubiprostone), dopamine antagonists (e.g. itopride,metaclopramide, domperidone), GABA-B agonists (e.g. baclofen, AGI 006),kappa opioid agonists (e.g. asimadoline), muscarinic M₁ and M₂antagonists (e.g. acotiamide), motilin agonists (e.g. mitemcinal),guanylate cyclase activators (e.g. MD-1100) and ghrelin agonists (e.g.Tzp 101, RC 1139).

In addition, the compounds of the invention can be combined with opioidtherapeutic agents. Such opioid agents include, but are not limited to,morphine, pethidine, codeine, dihydrocodeine, oxycontin, oxycodone,hydrocodone, sufentanil, fentanyl, remifentanil, buprenorphine,methadone, and heroin.

Numerous additional examples of such therapeutic agents are known in theart and any such known therapeutic agents may be employed in combinationwith the compounds of this invention. Secondary agent(s), when included,are present in a therapeutically effective amount, i.e. in any amountthat produces a therapeutically beneficial effect when co-administeredwith a compound of the invention. Suitable doses for the othertherapeutic agents administered in combination with a compound of theinvention are typically in the range of about 0.05 μg/day to about 100mg/day.

Accordingly, the pharmaceutical compositions of the invention optionallyinclude a second therapeutic agent as described above.

The following examples illustrate representative pharmaceuticalcompositions of the present invention:

Formulation Example A Hard Gelatin Capsules for Oral Administration

A compound of the invention (50 g), spray-dried lactose (200 g) andmagnesium stearate (10 g) are thoroughly blended. The resultingcomposition is loaded into a hard gelatin capsule (260 mg of compositionper capsule).

Formulation Example B Hard Gelatin Capsules for Oral Administration

A compound of the invention (20 mg), starch (89 mg), microcrystallinecellulose (89 mg), and magnesium stearate (2 mg) are thoroughly blendedand then passed through a No. 45 mesh U.S. sieve. The resultingcomposition is loaded into a hard gelatin capsule (200 mg of compositionper capsule).

Formulation Example C Gelatin Capsules for Oral Administration

A compound of the invention (10 mg), polyoxyethylene sorbitan monooleate(50 mg), and starch powder (250 mg) are thoroughly blended and thenloaded into a gelatin capsule (310 mg of composition per capsule).

Formulation Example D Tablets for Oral Administration

A compound of the invention (5 mg), starch (50 mg), andmicroscrystalline cellulose (35 mg) are passed through a No. 45 meshU.S. sieve and mixed thoroughly. A solution of polyvinylpyrrolidone (10wt % in water, 4 mg) is mixed with the resulting powders, and thismixture is then passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50-60° C. and passed through a No. 18 mesh U.S.sieve. Sodium carboxymethyl starch (4.5 mg), magnesium stearate (0.5 mg)and talc (1 mg), which have previously been passed through a No. 60 meshU.S. sieve, are then added to the granules. After mixing, the mixture iscompressed on a tablet machine to afford a tablet weighing 100 mg.

Formulation Example E Tablets for Oral Administration

A compound of the invention (25 mg), microcrystalline cellulose (400mg), fumed silicon dioxide (10 mg), and stearic acid (5 mg) arethoroughly blended and then compressed to form tablets (440 mg ofcomposition per tablet).

Formulation Example F Single-Scored Tablets for Oral Administration

A compound of the invention (15 mg), cornstarch (50 mg), croscarmellosesodium (25 mg), lactose (120 mg), and magnesium stearate (5 mg) arethoroughly blended and then compressed to form single-scored tablet (215mg of compositions per tablet).

Formulation Example G Suspension for Oral Administration

The following ingredients are thoroughly mixed to form a suspension fororal administration containing 100 mg of active ingredient per 10 mL ofsuspension:

Ingredients Amount Compound of the invention 0.1 g Fumaric acid 0.5 gSodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 gGranulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum k(Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg Distilledwater q.s. to 100 mL

Formulation Example H Dry Powder Composition

A micronized compound of the invention (1 mg) is blended with lactose(25 mg) and then loaded into a gelatin inhalation cartridge. Thecontents of the cartridge are administered using a powder inhaler.

Formulation Example J Injectable Formulation

A compound of the invention (0.1 g) is blended with 0.1 M sodium citratebuffer solution (15 mL). The pH of the resulting solution is adjusted topH 6 using 1 N aqueous hydrochloric acid or 1 N aqueous sodiumhydroxide. Sterile normal saline in citrate buffer is then added toprovide a total volume of 20 mL.

It will be understood that any form of the compounds of the invention,(i.e. free base, pharmaceutical salt, or solvate) that is suitable forthe particular mode of administration, can be used in the pharmaceuticalcompositions discussed above.

Utility

The 8-azabicyclooctane compounds of the invention are antagonists at themu opioid receptor and therefore are expected to be useful for treatingmedical conditions mediated by mu opioid receptors or associated with muopioid receptor activity, i.e. medical, conditions which are amelioratedby treatment with a mu opioid receptor antagonist. In particular, thecompounds of the invention are expected to be useful for treatingadverse effects associated with use of opioid analgesics, i.e. symptomssuch as constipation, decreased gastric emptying, abdominal pain,bloating, nausea, and gastroesophageal reflux, termed collectivelyopioid-induced bowel dysfunction. The mu opioid receptor antagonists ofthe invention are also expected to be useful for treating post-operativeileus, a disorder of reduced motility of the gastrointestinal tract thatoccurs after abdominal or other surgery. In addition, it has beensuggested that mu opioid receptor antagonist compounds may be used forreversing opioid-induced nausea and vomiting. Further, those mu opioidreceptor antagonists exhibiting some central penetration may be usefulin the treatment of dependency on, or addiction to, narcotic drugs,alcohol, or gambling, or in preventing, treating, and/or amelioratingobesity.

Since compounds of the invention increase motility of thegastrointestinal (GI) tract in animal models, the compounds are expectedto be useful for treating disorders of the GI tract caused by reducedmotility in mammals, including humans. Such GI motility disordersinclude, by way of illustration, chronic constipation,constipation-predominant irritable bowel syndrome (C-IBS), diabetic andidiopathic gastroparesis, and functional dyspepsia.

In one aspect, therefore, the invention provides a method of increasingmotility of the gastrointestinal tract in a mammal, the methodcomprising administering to the mammal a therapeutically effectiveamount of a pharmaceutical composition comprising apharmaceutically-acceptable carrier and a compound of the invention.

When used to treat disorders of reduced motility of the GI tract orother conditions mediated by mu opioid receptors, the compounds of theinvention will typically be administered orally in a single daily doseor in multiple doses per day, although other forms of administration maybe used. For example, particularly when used to treat post-operativeileus, the compounds of the invention may be administered parenterally.The amount of active agent administered per dose or the total amountadministered per day will typically be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compoundadministered and its relative activity, the age, weight, and response ofthe individual patient, the severity of the patient's symptoms, and thelike.

Suitable doses for treating disorders of reduced motility of the GItract or other disorders mediated by mu opioid receptors will range fromabout 0.0007 to about 20 mg/kg/day of active agent, including from about0.0007 to about 1.4 mg/kg/day. For an average 70 kg human, this wouldamount to from about 0.05 to about 100 mg per day of active agent.

In one aspect of the invention, the compounds of the invention are usedto treat opioid-induced bowel dysfunction. When used to treatopioid-induced bowel dysfunction, the compounds of the invention willtypically be administered orally in a single daily dose or in multipledoses per day. Preferably, the dose for treating opioid-induced boweldysfunction will range from about 0.05 to about 100 mg per day.

In another aspect of the invention, the compounds of the invention areused to treat post-operative ileus. When used to treat post-operativeileus, the compounds of the invention will typically be administeredorally or intravenously in a single daily dose or in multiple doses perday. Preferably, the dose for treating post-operative ileus will rangefrom about 0.05 to about 100 mg per day.

The invention also provides a method of treating a mammal having adisease or condition associated with mu opioid receptor activity, themethod comprising administering to the mammal a therapeuticallyeffective amount of a compound of the invention or of a pharmaceuticalcomposition comprising a compound of the invention.

As described above, compounds of the invention are mu opioid receptorantagonists. The invention further provides, therefore, a method ofantagonizing a mu opioid receptor in a mammal, the method comprisingadministering a compound of the invention to the mammal.

The mu opioid receptor antagonists of the invention are optionallyadministered in combination with another therapeutic agent or agents, inparticular, in combination with prokinetic agents acting via non-muopioid mechanisms. Accordingly, in another aspect, the methods andcompositions of the invention further comprise a therapeuticallyeffective amount of another prokinetic agent.

In addition, the compounds of the invention are also useful as researchtools for investigating or studying biological systems or samples havingmu opioid receptors, or for discovering new compounds having mu opioidreceptor activity. Any suitable biological system or sample having muopioid receptors may be employed in such studies which may be conductedeither in vitro or in vivo. Representative biological systems or samplessuitable for such studies include, but are not limited to, cells,cellular extracts, plasma membranes, tissue samples, mammals (such asmice, rats, guinea pigs, rabbits, dogs, pigs, etc.) and the like. Theeffects of contacting a biological system or sample comprising a muopioid receptor with a compound of the invention are determined usingconventional procedures and equipment, such as the radioligand bindingassay and functional assay described herein or other functional assaysknown in the art. Such functional assays include, but are not limitedto, ligand-mediated changes in intracellular cyclic adenosinemonophosphate (cAMP), ligand-mediated changes in activity of the enzymeadenylyl cyclase, ligand-mediated changes in incorporation of analogs ofguanosine triphosphate (GTP), such as [³⁵S]GTPγS (guanosine5′-O-(γ-thio)triphosphate) or GTP-Eu, into isolated membranes viareceptor catalyzed exchange of GTP analogs for GDP analogs, andligand-mediated changes in free intracellular calcium ions. A suitableconcentration of a compound of the invention for such studies typicallyranges from about 1 nanomolar to about 500 nanomolar.

When using compounds of the invention as research tools for discoveringnew compounds have mu opioid receptor activity, binding or functionaldata for a test compound or a group of test compounds is compared to themu opioid receptor binding or functional data for a compound of theinvention to identify test compounds that have superior binding orfunctional activity, if any. This aspect of the invention includes, asseparate embodiments, both the generation of comparison data (using theappropriate assays) and the analysis of the test data to identify testcompounds of interest.

Among other properties, compounds of the invention have been found toexhibit potent binding to mu opioid receptors and little or no agonismin mu receptor functional assays. Therefore, the compounds of theinvention are potent mu opioid receptor antagonists. Further, compoundsof the invention have demonstrated predominantly peripheral activity ascompared with central nervous system activity in animal models.Therefore, these compounds can be expected to reverse opioid-inducedreductions in GI motility without interfering with the beneficialcentral effects of analgesia. These properties, as well as the utilityof the compounds of the invention, can be demonstrated using various invitro and in vivo assays well-known to those skilled in the art.Representative assays are described in further detail in the followingexamples.

EXAMPLES

The following synthetic and biological examples are offered toillustrate the invention, and are not to be construed in any way aslimiting the scope of the invention. In the examples below, thefollowing abbreviations have the following meanings unless otherwiseindicated. Abbreviations not defined below have their generally acceptedmeanings.

Boc = tert-butoxycarbonyl (Boc)₂O = di-tert-butyl dicarbonate DABCO =1,4-diazaobicylco[2,2,2]octane triethylenediamine DCM = dichloromethaneDIPEA = N,N-diisopropylethylamine DMA = dimethylacetamide DMAP =dimethylaminopyridine DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide EtOAc = ethyl acetate EtOH = ethanol HATU =N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate MeCN = acetonitrile MeOH = methanol MeTHF =2-methyltetrahydrofuran MTBE = tert-butyl methyl ether PyBop =benzotriazol-1-yloxytripyrrolidino- phosphonium hexafluorophosphate TFA= trifluoroacetic acid THF = tetrahydrofuran

Reagents (including secondary amines) and solvents were purchased fromcommercial suppliers (Aldrich, Fluka, Sigma, etc.), and used withoutfurther purification. Reactions were run under nitrogen atmosphere,unless noted otherwise. Progress of reaction mixtures was monitored bythin layer chromatography (TLC), analytical high performance liquidchromatography (anal. HPLC), and mass spectrometry, the details of whichare given below and separately in specific examples of reactions.Reaction mixtures were worked up as described specifically in eachreaction; commonly they were purified by extraction and otherpurification methods such as temperature-, and solvent-dependentcrystallization, and precipitation. In addition, reaction mixtures wereroutinely purified by preparative HPLC: a general protocol is describedbelow. Characterization of reaction products was routinely carried outby mass and ¹H-NMR spectrometry. For NMR measurement, samples weredissolved in deuterated solvent (CD₃OD, CDCl₃, or DMSO-d₆), and ¹H-NMRspectra were acquired with a Varian Gemini 2000 instrument (300 MHz)under standard observation conditions. Mass spectrometric identificationof compounds was performed by an electrospray ionization method (ESMS)with an Applied Biosystems (Foster City, Calif.) model API 150 EXinstrument or an Agilent (Palo Alto, Calif.) model 1100 LC/MSDinstrument.

Preparation 1 Synthesis of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenola. Preparation of8-benzyl-3-exo-(3-methoxyphenyl)-8-azabicyclo[3.2.1]octan-3-ol

To a 3 L-3-necked flask fitted with an overhead stirrer and flushed withdry nitrogen was added cerous chloride powder (88.2 g, 0.35 mol). Thesolid was diluted with anhydrous tetrahydrofuran (500 mL) and cooled to0° C. To the suspension was added 1M 3-methoxyphenyl magnesium bromidein THF (360 mL, 0.36 mol) dropwise while the temperature was maintainedbelow 10° C. The resulting solution was stirred at 0° C. for 1.5 hours.A solution of 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (54.5 g, 0.25mol) in tetrahydrofuran (50 mL) was then added dropwise, whilemaintaining the internal temperature below 5° C. The resulting solutionwas stirred at 0° C. for 2 hours. The reaction was quenched with 10%aqueous acetic acid (400 mL) and stirred for 30 minutes at roomtemperature. Saturated sodium chloride solution (400 mL) was then addedand the resulting suspension was stirred at room temperature for 20hours to allow complete crystallization of product as the acetate salt.The crystals were filtered and washed with cold water (200 mL) followedby isopropyl acetate (200 mL) and dried under vacuum to give the titleintermediate as a white crystalline powder (91.1 g, 93% yield). (m/z):[M+H]⁺ calcd for C₂₁H₂₅NO₂ 324.20. Found, 324.5.

b. Preparation of8-benzyl-3-(3-methoxyphenyl)-8-azabicyclo[3.2.1]oct-2-ene

To a 1 L flask fitted with a magnetic stir bar was added8-benzyl-3-exo-(3-methoxy-phenyl)-8-azabicyclo[3.2.1]octan-3-ol as theacetate salt (80.4 g, 0.209 mol) followed by 6M aqueous hydrochlorideacid (300 mL). The reaction was heated to 70° C. for 2 hours. Thestirring was stopped and the reaction was diluted with dichloromethane(200 mL). The mixture was transferred to a reparatory funnel and thelayers were mixed, then allowed to settle. The organic layer was removedand saved. The aqueous layer was extracted with dichloromethane (2×200mL). The combined organic layers were washed with saturated aqueoussodium chloride solution (400 mL) and dried over anhydrous sodiumsulfate (30 g). Solvent was removed in vacuo to give the hydrochloridesalt of the title intermediate as a sticky yellow oil (65.4 g, 91%yield). (m/z): [M+H]⁺ calcd for C₂₁H₂₃NO 306.19. Found 306.3.

c. Preparation of 3-endo-(3-methoxyphenyl)-8-azabicyclo[3.2.1]octane

To a 1 L round-bottom flask containing of the product of the previousstep (65.4 g, 0.191 mol) was added ethanol (300 mL). The mixture wasstirred at room temperature until the intermediate was fully dissolved.To the solution was added palladium hydroxide (6.7 g, ˜10 wt %) as asolid, portionwise, with care. The reaction vessel was purged with drynitrogen and hydrogen was introduced carefully via balloon and needle.The hydrogen was bubbled through the solution for 10 minutes, and thesolution was allowed to stir overnight under a hydrogen atmosphere. Whenthe reaction was complete by HPLC, the hydrogen was removed from thereaction mixture and the vessel was purged with dry nitrogen for 10minutes. The reaction was then filtered through Celite (5 g), and theCelite cake was washed with ethanol (100 mL). The combined ethanolsolution was evaporated in vacuo, and the resulting residue wasdissolved in dichloromethane (400 mL). The organic layer was washed with3N sodium hydroxide (300 mL). The layers were separated and the aqueouslayer was extracted with dichloromethane (2×200 mL). Combined organiclayers were washed with aqueous sodium chloride (300 mL) and dried overpotassium carbonate (30 g). The drying agent was removed via filtrationand solvent was removed in vacuo to give the title intermediate as ayellow oil (27.6 g, 66% yield). (m/z): [M+H]⁺ calcd for C₁₄H₁₉NO 218.16.Found 218.3.

d. Synthesis of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenol

To a 1-L round bottom flask fitted with a magnetic stirbar and anaddition funnel was added the product of the previous step (27.6 g,0.127 mol) and dichloromethane (300 mL). The reaction was cooled in adry ice/acetone bath to −78° C. To the cooled reaction was added borontribromide (1M solution in dichloromethane, 152 mL, 0.152 mol). Thereaction was permitted to warm slowly to room temperature over a periodof 20 hours. The reaction was placed on an ice bath and methanol (100mL) was carefully added to quench the reaction. The solvent was removedin vacuo to give a crunchy beige solid. The solid was redissolved inmethanol (100 mL). The solvent was removed in vacuo to give a crunchybeige solid. The solid was redissolved again in methanol (100 mL). Thesolvent was removed in vacuo to give a crunchy beige solid which wasthen dried under vacuum for 2 hours. The dried solid was then suspendedin ethanol (110 mL) and the solution was heated on an oil bath to 80° C.To the hot solution was added just enough methanol to dissolve all thesolid material (72 mL). The solution was cooled slowly to roomtemperature, and white crystals of the hydrobromide salt of the titleintermediate were allowed to form. The solution was then further cooledto −20° C. in the freezer for one hour. The crystallization was warmedto room temperature and the crystals were collected via filtration. Thewhite crystals were washed with cold ethanol (35 mL) and dried underhouse vacuum to give the hydrobromide salt of the title intermediate asa white powder (19.5 g, 54% yield). The mother liquor was evaporated togive a crunchy beige solid. The solid was redissolved in ethanol (30 mL)and heated to 80° C. A clear brown solution formed. The solution wascooled to room temperature and then to −20° C. for one hour. Crystalswere then collected via filtration, washed with cold ethanol (10 mL),and dried under vacuum to give a second crop of crystals (5.5 g, 15%yield). (m/z): [M+H]⁺ calcd for C₁₃H₁₇NO 204.14. Found, 204.4.

Preparation 2 Synthesis of3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide a. Preparation of3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

To a 500 mL reaction flask containing the hydrobromide salt of3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenol (24.8 g, 0.087 mol) wasadded dichloromethane (200 mL) under a dry nitrogen atmosphere. Theslurry was cooled to 0° C. To the slurry was then addedN,N-diisopropylethylamine (22.75 mL, 0.13 mol) and di-tert-butyldicarbonate (19.03 g, 0.087 mol) in one portion as a solid. The reactionwas allowed to warm to room temperature over a period of 16 hours. Whenthe reaction was complete by HPLC, the reaction mixture (now a clearlight brown solution) was transferred to a separatory funnel and dilutedwith isopropyl acetate (200 mL). The organic mixture was washed withsaturated aqueous sodium bicarbonate (300 mL). The organic layer wasremoved and the aqueous layer was extracted with isopropyl acetate (200mL). The combined organic layers were washed with aqueous sodiumchloride solution (300 mL), the layers were separated, and the organiclayer was dried over anhydrous sodium sulfate (20 g). Solvent wasremoved in vacuo to afford the title intermediate as a white solid (27.1g, >100% yield). (m/z): [M+H]⁺ calcd for C₁₈H₂₅NO₃ 304.19. Found 304.3,248.3 (parent—tert-butyl)

b. Preparation of3-endo-(3-trifluoromethanesulfonyloxy-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

To a 500 mL reaction flask fitted with a magnetic stirbar and purgedwith dry nitrogen was added the product of the previous step (27.1 g,0.089 mol) and dichloromethane (250 mL). The solution was cooled to 0°C. on an ice bath. To the cold solution was added triethylamine (12.4mL, 0.097 mol) and trifluoromethane sulfonyl chloride (9.43 mL, 0.097mol) dropwise while maintaining the internal temperature below 10° C. Tothis reaction was added solid 4-N,N-dimethylaminopyridine (0.544 g, 4.46mmol) in one portion. The reaction was warmed to room temperature andstirred for 30 minutes. The final solution was transferred to areparatory funnel. The organic layer was washed with saturated aqueoussodium bicarbonate (200 mL) and saturated aqueous sodium chloride (200mL). The organic layer was separated and dried over anhydrous sodiumsulfate (20 g). Drying agent was removed via filtration and solvent wasremoved in vacuo to yield the title intermediate as a clear oil (38.4 g,98% yield). (m/z): [M+H]⁺ calcd for C₁₉H₂₄F₃NO₅S 436.14. Found 436.2,380.3 (parent—tert-butyl).

c. Preparation of3-endo-(3-cyanophenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

To a 1 L round bottom flask fitted with a magnetic stirbar and purgedwith dry nitrogen was added the product of the previous step (38.4 g,88.3 mmol) and dimethylformamide (320 mL). The solution was stirred for5 minutes to dissolve all starting material, then degassed under vacuum.A dry nitrogen atmosphere was again introduced. To the degassed solutionwas added zinc cyanide (15.5 g, 132 mmol) andtetrakis(triphenylphosphine)palladium (0) (5.1 g, 4.41 mmol) together assolids in one portion. The reaction was again degassed under vacuum anda dry nitrogen atmosphere was introduced. The reaction was heated to 80°C. for 4 hours. The reaction was cooled to room temperature and dilutedwith isopropyl acetate (500 mL). The resulting cloudy solution wasfiltered through Celite (10 g). The resulting organic solution waswashed with saturated aqueous sodium bicarbonate (400 mL) and saturatedaqueous sodium chloride (400 mL). The organic layer was separated anddried over anhydrous sodium sulfate (30 g). Drying agent was removed viafiltration and solvent was removed in vacuo to give crude titleintermediate as waxy brown crystals (29.9 g, >100% yield). (m/z): [M+H]⁺calcd for C₁₉H₂₄N₂O₂ 313.19. Found 313.3, 257.3 (parent—tert-butyl).

d. Synthesis of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-benzamide

To a 15 mL round bottom flask fitted with a magnetic stirbar and areflux condenser was added3-endo-(3-cyanophenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (500 mg, 1.60 mmol) as a solid followed bytrifluoroacetic acid (4 mL). To the solution was added concentratedsulfuric acid (440 μL, 5.0 equiv.). The reaction was heated to 65° C.for 10 hours. The reaction was poured into a solution of saturatedaqueous sodium chloride (70 mL) and transferred to a separatory funnel.The aqueous layer was washed with isopropyl acetate (50 mL) to removeresidual triphenylphosphine oxide from the previous step. To the aqueouslayer was added 3 N aqueous sodium hydroxide (15 mL) to adjust the pH to14. The aqueous layer was extracted with tetrahydrofuran (2×50 mL).Combined organic layers were dried over anhydrous sodium sulfate (3 g).Drying agent was removed via filtration and the solvent was removed invacuo to give the title compound as a crunchy, partially crystallinefoam (300 mg, 79% yield). (m/z): [M+H]⁺ calcd for C₁₄H₁₈N₂O 231.15.Found 231.2.

Preparation 3 a. Preparation of 2-cyclohexyl-1-formylethyl)-carbamicacid tert-butyl ester

A solution of 2-cyclohexyl-1-hydroxymethylethyl-carbamic acid tert-butylester (1.0 g, 3.88 mmol) in N,N-diisopropylethylamine (2.71 mL, 15.5mmol) and dichloromethane (15 mL) was cooled to −20° C. and a solutionof sulfur trioxide-pyridine complex (2.47 g, 15.5 mmol) in dimethylsulfoxide (15 mL) was added. The reaction mixture was stirred for 4 hand then allowed to warm to room temperature. To the reaction mixturewas added dichloromethane (40 mL). The reaction mixture was washed with1.0N HCl and with water. The organic layer was collected, dried overanhydrous sodium sulfate, filtered, and concentrated to give the titleintermediate as an oil (900 mg) which was used without furtherpurification.

b. Synthesis of3-endo-[8-(2-amino-3-cyclohexylpropyl)-8-aza-bicyclo[3.2.1]oct-3-yl]phenol

To a solution of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)phenol hydrobromide(0.25 g, 0.88 mmol) and 2-cyclohexyl-1-formylethyl)carbamic acidtert-butyl ester (0.25 g, 0.97 mmol) in N,N-diisopropylethylamine (150uL, 0.89 mol) and dichloromethane (10 mL) was added sodiumtriacetoxyborohydride (0.22 g, 0.10 mmol). The reaction mixture wasstirred for 12 h. Trifluoroacetic acid (10 mL) was added and thereaction mixture was stirred for 3 h. To the reaction mixture was addedwater (15 mL). The aqueous layer was basified to pH=10 with 6.0 N NaOH.The product was extracted with ethyl acetate (20 mL). The organic layerwas collected, dried over anhydrous sodium sulfate, filtered, andconcentrated to give the title compound.

(m/z): [M+H]⁺ calcd for C₂₂H₃₄N₂O, 343.27. Found 343.5.

c. Synthesis of3-endo-[8-(2-amino-3-cyclohexylpropyl)-8-azabicyclo[3.2.1]oct-3-yl]benzamide

Following the procedure of step b using the 8-azbicyclooctane benzamideintermediate of Preparation 2, the title compound was prepared. (m/z):[M+H]⁺ calcd for C₂₃H₃₅N₃O, 370.28. Found 370.4.

Preparation 4

Following the procedure of Preparation 3, step b, using(1-formyl-2-phenylethyl)-carbamic acid tert-butyl ester and theappropriate 8-azabicyclooctane intermediate, the following compoundswere prepared:

-   3-endo-[8-(2-amino-3-phenylpropyl)-8-azabicyclo[3.2.1]oct-3-yl]phenol    (m/z): [M+H]⁺ calcd for C₂₂H₂₈N₂O, 337.22. Found 337.5.-   3-endo-[8-(2-amino-3-phenylpropyl)-8-azabicyclo[3.2.1]oct-3-yl]benzamide    (m/z): [M+H]⁺ calcd for C₂₃H₂₉N₃O, 364.23. Found 365.0.

Preparation 5 Synthesis of3-endo-[8-(3-cyclohexyl-2-methylaminopropyl)-8-azabicyclo[3.2.1]oct-3-yl]benzamidea. Preparation of 2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acidmethyl ester

To a solution of 2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acid(3.0 g, 11.1 mmol) and potassium carbonate (1.5 g, 11.1 mmol) inN,N-dimethylformamide (20 mL) was added methyl iodide (0.795 μL; 12.1mmol). The reaction mixture was stirred at room temperature overnight.To the reaction mixture was added ethyl acetate (100 mL) and thesolution was washed with water (3×100 mL). The organic layer was driedover anhydrous sodium sulfate, filtered, and concentrated to give thetitle intermediate as an oil (3.1 g) which was used directly in the nextstep.

b. Preparation of (2-cyclohexyl-1-formylethyl)methyl-carbamic acidtert-butyl ester

To a solution of 2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acidmethyl ester (3.1 g) and methyl iodide (1.45 mL, 22.0 mmol) inN,N-Dimethylformamide (20 mL) cooled to 0° C. was added dry sodiumhydride (320 mg, 13.3 mmol) in three portions. The reaction was stirredat room temperature for 2 h. To the reaction mixture was carefully addedmethanol (10 mL) and then ethyl acetate (100 mL) and the solution waswashed with water (3×100 mL). The organics were dried over anhydroussodium sulfate, filtered, and concentrated to give an oil (3.2 g). Theresulting oil was dissolved in toluene (50 mL) and cooled to −78° C. Tothe cooled solution, 1.0 N diisobutylaluminum hydride in toluene (16.5mL, 16.5 mmol) was added dropwise over 15 min. The reaction mixture wasstirred at −78° C. for 2 h. Methanol (10 mL) was carefully added and thereaction mixture was warmed to room temperature and washed with 10%acetic acid in water (2×100 mL) followed by brine (100 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude product was purified by flash columnchromatography eluting with 10% ethyl acetate in hexanes to provide thetitle intermediate (2.0 g).

c. Synthesis of3-endo-[8-(3-cyclohexyl-2-methylaminopropyl)-8-azabicyclo[3.2.1]oct-3-yl]benzamide

Following the procedure of Preparation 3, step b, using the intermediateof the previous step, the title compound was prepared. (m/z): [M+H]⁺calcd for C₂₄H₃₇N₃O, 384.29. Found 384.3.

Preparation 6 Synthesis of3-endo-[8-(2-methylamino-3-phenylpropyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-benzamide

Following the procedure of Preparation 5, steps b and c, using reagent2-tert-butoxycarbonylamino-3-phenylpropionic acid methyl ester, thetitle compound was prepared. (m/z): [M+H]⁺ calcd for C₂₄H₃₁N₃O, 378.25.Found 378.2.

Preparation 7 Synthesis of3-endo-[8-(2-aminoindan-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-phenola. Preparation of(2-aminoindan-2-yl)-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]methanone

To a solution of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-phenolhydrobromide (0.51 g, 1.8 mmol), N-Boc-2-aminoindane-2-carboxylic acid(0.50 g, 1.8 mmol), and N,N-diisopropylethylamine (941 μL, 5.4 mmol) inN,N-dimethylformamide (3.0 mL) was addedN,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uraniumhexafluorophosphate (HATU) (0.779 g, 2.1 mmol). The reaction mixture wasstirred for 2 h at room temperature, diluted with ethyl acetate (30 mL)and washed with LON HCl (3×30 mL). The organic layer was collected,dried over anhydrous sodium sulfate, filtered, and concentrated. Theresulting solid was stirred in dichloromethane (3 mL) andtrifluoroacetic acid (8 mL) for 1 h. The reaction mixture wasconcentrated. The resulting material was dissolved in water (10 mL) andbasified to pH=10 with 6.0N NaOH. The product was extracted with ethylacetate, dried over anhydrous sodium sulfate, filtered, andconcentrated. The resulting solid was used in the next step withoutfurther purification. (m/z): [M+H]⁺ calcd for C₂₃H₂₆N₂O₂, 363.20. Found363.3.

b. Synthesis of3-endo-[8-(2-aminoindan-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-phenol

To a solution of the product of the previous step in tetrahydrofuran (10mL) was added 2.0 N borane dimethylsulfide complex in tetrahydrofuran(2.7 mL, 5.4 mmol). The reaction mixture was stirred at 55° C. for 2 hand cooled to room temperature. To the reaction mixture was carefullyadded methanol (10 mL). The reaction mixture was stirred for 15 min andconcentrated. The crude oil was dissolved in methanol (5 mL) and 4.0 NHCl in dioxane (5 mL). The reaction mixture was concentrated andpurified by preparative HPLC to give the title compound as the bis TFAsalt (405 mg). (m/z): [M+H]⁺ calcd for C₂₃H₂₈N₂O, 349.22. Found 349.3.

Preparation 8 Synthesis of3-endo-[8-(2-amino-4-phenylbutyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-phenol

Following the procedure of Example 3 below,2-tert-butoxycarbonylamino-4-phenyl-butyric acid was reacted with3-endo-(8-azabicyclo[3.2.1]oct-3-yl)phenol hydrobromide to form theintermediate2-amino-1-[3-endo-(3-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-4-phenyl-butan-1-one,which was reduced according to the procedure of Preparation 7 step b toprovide the title compound. (m/z): [M+]⁺ calcd for C₂₃H₃₀N₂O, 351.24.Found 351.

Preparation 9 Synthesis of3-endo-[8-(2-amino-4-cyclohexylbutyl)-8-aza-bicyclo[3.2.1]oct-3-yl]phenola. Preparation of 3-cyclohexyl-1-formylpropyl)carbamic acid tert-butylester

To a solution of 2-amino-4-cyclohexyl-butyric acid ethyl esterhydrochloride (5.0 g; 0.02 mol) and triethylamine (2.78 mL; 0.02 mol) indichloromethane (50 mL) was added dropwise a solution of di-tert-butyldicarbonate (4.36 g; 0.02 mol) in dichloromethane (20 mL). The reactionmixture was stirred for 2 h and washed with 10% acetic acid in water(2×50 mL) followed by water (2×50 mL). The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated to give an oil.

To the solution of the resulting oil and ethanol (40 mL) was added infour portions sodium borohydride (740 mg, 0.02 mol) over 5 min. Thereaction mixture was stirred at room temperature for 6 h. To thereaction mixture was added 10% acetic acid in water. The reactionmixture was stirred until hydrogen evolution ceased and thenconcentrated. The crude oil was dissolved with ethyl acetate (75 mL) andwashed with water (2×75 mL). The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated.

To a solution of the crude product and N,N-diisopropylethylamine (14 mL;0.08 mol) in dichloromethane (50 mL) was added a solution of pyridinesulfur trioxide complex (12.7 g; 0.08 mol) in dimethyl sulfoxide (50 mL)at −20° C. The reaction mixture was stirred for 2 h and diluted withethyl acetate (150 mL). The reaction mixture was washed with 1.0N HCl(3×100 mL). The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated to give an oil (5.8 g) which was used in thenext step without further purification.

b. Synthesis of3-endo-[8-(2-amino-4-cyclohexylbutyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-phenol

Following the procedure of Preparation 3 step b using the intermediateof the previous step, the crude title compound was prepared. The crudeproduct was purified by preparative HPLC to give the title compound asthe bis TFA salt. The resulting TFA salt was dissolved in 0.1N HCl (100mL) and lyophilized to give the his HCl salt.

(m/z): [M+H]⁺ calcd for C₂₃H₃₆N₂O, 357.25. Found 357.3

Preparation 10 a. Preparation of (1-cyclohexyl-3-oxopropyl)carbamic acidtert-butyl ester

To a solution of (1-cyclohexyl-3-hydroxypropyl)carbamic acid tert-butylester (500 mg; 1.9 mmol) and N,N-diisopropylethylamine (1.35 mL; 7.8mol) in dichloromethane (5 mL) was added a solution of pyridine sulfurtrioxide complex (1.25 g; 7.8 mmol) in dimethyl sulfoxide (5 mL) at −20°C. The reaction mixture was stirred for 2 h and diluted withdichloromethane (20 mL). The reaction mixture was washed with 10% aceticacid in water (2×15 mL) The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated. The crude oil was used inthe next step without further purification.

b. Synthesis of3-endo-[8-(3-amino-3-cyclohexylpropyl)-8-azabicyclo[3.2.1]oct-3-yl]-phenol

Following the procedure of Preparation 3 step b, using the intermediateof the previous step, the title compound was prepared. (m/z): [M+H]⁺calcd for C₂₂H₃₄N₂O, 343.27. Found 343.4.

c. Synthesis of3-endo-[8-(3-amino-3-cyclohexylpropyl)-8-azabicyclo[3.2.1]oct-3-yl]-benzamide

Following the procedure of Preparation 3 step b, using the intermediateof step a and the 8-azabicyclooctane benzamide intermediate, the titlecompound was prepared. (m/z): [M+H]⁺ calcd for C₂₃H₃₅N₃O, 370.28. Found370.5

d. Synthesis of3-endo-[8-(3-amino-3-phenylpropyl)-8-azabicyclo[3.2.1]oct-3-yl]benzamide

Using similar procedures, the title compound was prepared. (m/z): [M+H]⁺calcd for C₂₃H₂₉N₃O, 364.23. Found 364.4.

Preparation 11 Synthesis of2-benzyl-3-[3-endo-(3-carbamoylphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-propionicacid ethyl ester a. Preparation of ethyl (phenylmethyl)propanedioic acid

To a solution of diethyl benzylmalonate (20.0 g, 80 mmol) in ethanol(500 mL) was added potassium hydroxide (4.7 g, 84 mmol) as pellets. Themixture was stirred at room temperature for 24 h, and concentrated todryness in vacuo. The residue was dissolved in water (300 mL),transferred to a separatory funnel, and washed with ether (2×150 mL).The aqueous solution was acidified to pH˜2 by adding conc. HCl, andextracted with ether (2×400 mL). The organic layer was dried over MgSO₄,filtered and evaporated to dryness in vacuo, yielding the title compoundas an oil residue (16.9 g, 95%) which was used without furtherpurification.

b. Preparation of 2-benzyl-acrylic acid ethyl ester

The product of the previous step (10 g, 45 mmol) in a round bottomedflask was cooled in an ice bath and then diethylamine (4.8 mL) and 37%aqueous formaldehyde solution (4.8 mL) was added over 10 min withstirring. After stirring for 7 h, the mixture was diluted with water(100 mL), and extracted with ether (500 mL). The organic layer waswashed with 2M HCl (300 mL), saturated sodium bicarbonate (300 mL), andbrine solution, dried over MgSO₄, and evaporated to dryness, to providethe title compound as an oil (6.07 g, 71%). ¹H NMR (CD₃OD) δ (ppm)7.15-7.08 (m, 3H), 7.07-7.05 (m, 2H), 6.07 (d, J=1.5 Hz, 1H), 5.41 (d,J=1.5 Hz, 1H), 4.06-3.99 (q, J=6.6 Hz, 2H), 3.50 (s, 2H), 1.14-1.07 (t,J=6.6 Hz, 2H).

c. Preparation of2-benzyl-3-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-propionicacid

A solution of 2-benzyl-acrylic acid ethyl ester (1.77 g; 9.3 mmol),3-endo-(8-aza-bicyclo[3.2.1]oct-3-yl)phenol hydrobromide (2.65 g, 9.3mmol) and N,N-diisopropylethylamine (6.5 mL, 37.3 mmol) in ethanol (25mL) was stirred overnight at 70° C. The reaction mixture was cooled toroom temperature and concentrated. The reaction mixture was extractedwith ethyl acetate and washed with saturated Na₂CO₃. The organic layerwas collected, dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude product was purified by flash columnchromatography eluting with dichloromethane and methanol to provide thetitle compound (2.8 g). (m/z): [M+H]⁺ calcd for C₂₅H₃₁NO₃, 394.23. Found394.3

e. Synthesis of2-benzyl-3-[3-endo-(3-carbamoylphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-propionicacid ethyl ester

To solution of the product of the previous step (2.8 g; 7.1 mmol) andtriethylamine (1.1 mL; 7.9 mmol) in dichloromethane (20 mL) cooled to 0°C. was added dropwise trifluoromethanesulfonyl chloride (0.827 mL; 7.8mmol). To the reaction mixture was added 4-dimethylaminopyridine (43 mg;0.35 mmol). The reaction mixture was warmed to room temperature, stirredfor 30 min, and washed with water (2×20 mL). The organic layer wascollected, dried over anhydrous sodium sulfate, filtered, andconcentrated.

The resulting crude oil was dissolved in N,N-dimethylformamide (30 mL)and purged thoroughly with nitrogen. To the reaction mixture was addedzinc cyanide (1.25 g; 10.6 mmol; andtetrakis(triphenylphosphine)palladium(0) (0.411 g; 0.355 mmol). Thereaction mixture was stirred at 85° C. for 3 h, cooled to roomtemperature and filtered through Celite. The product was extracted withethyl acetate (50 mL) and washed with water (3×50 mL). The organic layerwas collected, dried over anhydrous sodium sulfate, filtered, andconcentrated.

To a solution of the resulting crude oil and potassium carbonate (240mg, 1.7 mmol) in dimethyl sulfoxide (25 mL) was added 30% hydrogenperoxide (5.5 mL). The reaction mixture was stirred for 3 h, cooled to0° C., and the reaction was quenched with Na₂S₂O₅ maintaining aninternal temperature of 25° C. The mixture was basified to pH=6 with 6.0N NaOH. The product was extracted with ethyl acetate (200 mL) and washedwith water (100 mL). The organic layer was washed with saturated NaClsolution (2×100 mL). The organic layer was collected, dried overanhydrous sodium sulfate, filtered, and concentrated.

The crude oil was dissolved in ethanol (10 mL) and 10.0N NaOH (0.7 mL)and stirred overnight at room temperature. The reaction was concentratedand the product was purified by preparative HPLC to give the titlecompound as the TFA salt.

(m/z): [M+H]⁺ calcd for C₂₄H₂₈N₂O₃, 393.21. Found 393.2.

Example 1 Synthesis of cyclohexanecarboxylic acid{1-cyclohexylmethyl-2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl}amide

To a solution of3-endo-[8-(2-amino-3-cyclohexylpropyl)-8-azabicyclo[3.2.1]oct-3-yl]phenol(20 mg, 0.058 mmol) and triethylamine (8.1 μL, 0.058 mmol) indichloromethane (1.0 mL) was added cyclohexanecarbonyl chloride (7.9 μL,0.058 mmol). The reaction mixture was stirred for 12 h, concentrated,and purified by preparative HPLC to give the title compound as the TFAsalt (26.8 mg). (m/z): [M+H]⁺ calcd for C₂₉H₄₄N₂O₂, 453.27. Found 453.4.

Example 2 Synthesis ofN-{1-cyclohexylmethyl-2-[3-endo-(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-hydroxyacetamide

To a solution of3-endo-[8-(2-amino-3-cyclohexylpropyl)-8-aza-bicyclo[3.2.1]oct-3-yl]phenol(50 mg, 0.15 mmol), succinamic acid (7 mg, 0.06 mmol), and triethylamine(20 μL, 0.14 mmol) in dichloromethane (1.0 mL) was added acetoxyacetylchloride (16 μL, 0.15 mmol). The reaction mixture was stirred for 30min, concentrated and diluted with methanol (1 mL). To the reactionmixture was added 6.0N NaOH (150 μL). The reaction mixture was stirredovernight, concentrated, and purified by preparative HPLC to give thetitle compound as the TFA salt (11.3 mg). (m/z): [M+H]⁺ calcd forC₂₄H₃₆N₂O₃, 401.27. Found 401.2.

Example 3 Synthesis ofN-{1-cyclohexylmethyl-2-[3-endo-(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}succinamide

To a solution of3-endo-[8-(2-amino-3-cyclohexylpropyl)-8-aza-bicyclo[3.2.1]oct-3-yl]phenol(20 mg, 0.060 mmol) and N,N-diisopropylethylamine (10 μL, 0.058 mmol) inN,N-dimethylformamide (1.0 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uraniumhexafluorophosphate (33 mg, 0.087 mmol). The reaction mixture wasstirred overnight, concentrated, and purified by preparative HPLC togive the title compound as the TFA salt (22.8 mg). (m/z): [M+H]⁺ calcdfor C₂₆H₃₉N₃O₃, 442.30. Found 442.2.

Example 4 Synthesis of1-cyclohexylmethyl-3-{1-cyclohexylmethyl-2-[3-endo-(3-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}urea

To a solution of3-endo-[8-(2-amino-3-cyclohexylpropyl)-8-aza-bicyclo[3.2.1]oct-3-yl]phenol(50 mg, 0.15 mmol) and N,N-diisopropylethylamine (10 μL, 0.058 mmol) inacetonitrile (1.0 mL) was added cyclohexane methyl isoscyanate (8.3 μL,0.058 mmol). The reaction mixture was stirred overnight at 50° C.,concentrated, and purified by preparative HPLC to give the titlecompound as the TFA salt (20.5 mg). (m/z): [M+H]⁺ calcd for C₃₀H₄₇N₃O₂,482.37. Found 482.4.

Example 5 Synthesis ofN-{1-cyclohexylmethyl-2-[3-endo-(3-hydroxy-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-methyl-benzenesulfonamide

To a solution of3-endo-[8-(2-amino-3-cyclohexylpropyl)-8-aza-bicyclo[3.2.1]oct-3-yl]phenol(20 mg, 0.058 mmol) and triethylenediamine (6.5 mg, 0.058 mmol) indichloromethane (1 mL) was added p-toluenesulfonyl chloride. Thereaction mixture was stirred overnight, concentrated, and purified bypreparative HPLC to give the title compound as the TFA salt (13.6 mg).(m/z): [M+H]⁺ calcd for C₂₉H₄₀N₂O₃S, 497.28. Found 497.2.

Example 6 Synthesis of3-endo-{8-[(S)-2-(S)-1-carbamoyl-3-methyl-butylcarbamoyl)-3-phenylpropyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamideand3-endo-{8-[(R)-2-((S)-1-carbamoyl-3-methylbutylcarbamoyl)-3-phenyl-propyl]-8-azabicyclo[3.2.1]oct-3-yl}benzamide

To a solution of2-benzyl-3-[3-endo-(3-carbamoylphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-propionicacid (30 mg; 0.058 mmol), (S)-2-amino-4-methylpentanoic acid amidehydrochloride (11.8 mg, 0.071 mmol), and N,N-diisopropylethylamine (20μL, 0.115 mmol) in N,N-dimethylformamide (0.5 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uraniumhexafluorophosphate (30 mg, 0.087 mmol). The reaction was stirredovernight. The reaction mixture was stirred overnight, concentrated, andthe diastereomers (23.6 mg) were purified by preparative HPLC to givethe title compounds as their TFA salts. (m/z): [M+H]⁺ calcd forC₃₀H₄₀N₄O₃, 505.31. Found 505.2.

Examples 7 to 139

Using the intermediates of Preparations 1 to 11 and processes similar tothose of Examples 1 to 6, the compounds of Tables 1 to 15 were prepared.

TABLE 1

Calc. Obs. Ex [M + [M + No R¹ R³ R^(a) Formula H]⁺ H]⁺ 7 OH(CH₂)₂-chexyl H C₃₁H₄₈N₂O₂ 481.37 481.4 8 OH (CH₂)₂C(O)OH H C₂₆H₃₈N₂O₄443.28 443.2 9 OH phenyl H C₂₉H₃₈N₂O₂ 447.29 447.2 10 OH (CH₂)₂-phenyl HC₃₁H₄₂N₂O₂ 475.32 475.2 11 OH CH₂N(CH₃)₂ H C₂₆H₄₁N₃O₂ 428.32 428.2 12 OHCH₃ H C₂₄H₃₆N₂O₂ 385.28 385.2 13 OH 4-S(O)₂NH₂- H C₂₉H₃₉N₃O₄S 526.27526.2 phenyl 14 C(O)NH₂ chexyl H C₃₀H₄₅N₃O₂ 480.35 480.4 15 C(O)NH₂(CH₂)₂-chexyl H C₃₂H₄₉N₃O₂ 508.38 508.4 16 C(O)NH₂ CH₂OH H C₂₅H₃₇N₃O₃428.28 428.2 17 C(O)NH₂ phenyl H C₃₀H₃₉N₃O₂ 474.30 474.2 18 C(O)NH₂(CH₂)₂-phenyl H C₃₂H₄₃N₃O₂ 502.34 502.2 19 C(O)NH₂ CH₂-chexyl HC₃₁H₄₈N₄O₂ 509.38 509.4 20 C(O)NH₂ CH₂-phenyl H C₃₁H₄₂N₄O₂ 503.33 503.221 C(O)NH₂ (CH₂)₂—C(O)NH₂ H C₂₇H₄₀N₄O₃ 469.31 469.2 22 C(O)NH₂ CH₂OH CH₃C₂₆H₃₉N₃O₃ 442.30 442.4 23 C(O)NH₂ (CH₂)₃C(O)OH CH₃ C₂₉H₄₃N₃O₄ 498.33498.4 24 C(O)NH₂ CH₂S(O)₂CH₃ CH₃ C₂₇H₄₁N₃O₄S 504.28 504.4

TABLE 2

Ex Calc. Obs. No R¹ R⁵ Formula [M + H]⁺ [M + H]⁺ 25 OH CH₂-phenylC₃₀H₄₁N₃O₂ 476.32 476.2 26 OH (CH₂)₄CH₃ C₂₈H₄₅N₃O₂ 456.35 456.2 27C(O)NH₂ CH(CH₃)₂ C₂₈H₄₄N₄O₂ 469.35 469.4

TABLE 3

Calc. Obs. Ex [M + [M + No R¹ R³ R^(a) Formula H]⁺ H]⁺ 28 OH CH₂OH HC₂₄H₃₀N₂O₃ 395.23 395.3 29 OH chexyl H C₂₉H₃₈N₂O₂ 447.29 447.4 30 OH(CH₂)₂-chexyl H C₃₁H₄₂N₂O₂ 475.32 475.2 31 OH (CH₂)₂C(O)OH H C₂₆H₃₂N₂O₄437.24 437.2 32 OH phenyl H C₂₉H₃₂N₂O₂ 441.25 441.2 33 OH (CH₂)₂-phenylH C₃₁H₃₆N₂O₂ 469.28 468.6 34 OH CH₂N(CH₃)₂ H C₂₆H₃₅N₃O₂ 422.27 422.2 35OH CH₃ H C₂₄H₃₀N₂O₂ 379.23 379.2 36 OH (CH₂)₂C(O)NH₂ H C₂₆H₃₃N₃O₃ 436.25436.2 37 OH 4-S(O)₂NH₂- H C₂₉H₃₃N₃O₄S 520.22 520.2 phenyl 38 C(O)NH₂(CH₂)₂-chexyl H C₃₂H₄₃N₃O₂ 502.34 502.2 39 C(O)NH₂ chexyl H C₃₀H₃₉N₃O₂474.30 474.2 40 C(O)NH₂ CH₂OH H C₂₅H₃₁N₃O₃ 422.24 422.2 41 C(O)NH₂(CH₂)₂C(O)NH₂ H C₂₇H₃₄N₄O₃ 463.26 462.2 42 C(O)NH₂ phenyl H C₃₀H₃₃N₃O₂468.26 468.2 43 C(O)NH₂ (CH₂)₂-phenyl H C₃₂H₃₇N₃O₂ 496.29 496.2 44C(O)NH₂ CH₂OH CH₃ C₂₆H₃₃N₃O₃ 436.25 436.2 46 C(O)NH₂ (CH₂)₃C(O)OH CH₃C₂₉H₃₇N₃O₄ 492.28 492.2 47 C(O)NH₂ CH₂S(O)₂CH₃ CH₃ C₂₇H₃₅N₃O₄S 498.24498.2

TABLE 4

Ex Calc. Obs. No R¹ R⁵ R^(a) Formula [M + H]⁺ [M + H]⁺ 48 OH CH₂-chexylH C₃₀H₄₁N₃O₂ 476.32 476.2 49 OH CH₂-phenyl H C₃₀H₃₅N₃O₂ 470.27 470.2 50OH S(O)₂-phenyl H C₂₉H₃₃N₃O₄S 520.22 520.2 51 C(O)NH₂ CH₂-chexyl HC₃₁H₄₂N₄O₂ 503.33 503.2 52 C(O)NH₂ CH₂-phenyl H C₃₁H₃₆N₄O₂ 497.28 497.253 C(O)NH₂ CH(CH₃)₂ CH₃ C₂₈H₃₈N₄O₂ 463.30 463.4

TABLE 5

Ex Calc. Obs. No R¹ Q Formula [M + H]⁺ [M + H]⁺ 54 OH C(O)-phenylC₃₀H₃₂N₂O₂ 453.25 453.2 55 OH C(O)(CH₂)₂- C₃₂H₃₆N₂O₂ 481.28 481.2 phenyl56 OH C(O)-chexyl C₃₀H₃₈N₂O₂ 459.29 459.2 57 OH C(O)(CH₂)₂- C₃₂H₄₂N₂O₂487.32 487.3 chexyl 58 OH C(O)NHCH₂- C₃₁H₃₅N₃O₂ 482.27 482.2 phenyl 59OH C(O)NHCH₂- C₃₁H₄₁N₃O₂ 488.32 488.2 chexyl 60 OH C(O)CH₂OH C₂₅H₃₀N₂O₃407.23 407.2 61 OH S(O)₂CH₃ C₂₄H₃₀N₂O₃S 427.20 457.2 62 OH S(O)₂-phenylC₂₉H₃₂N₂O₃S 489.21 489.2

TABLE 6

Ex Calc. Obs. No R¹ R³ Formula [M + H]⁺ [M + H]⁺ 63 OH phenyl C₃₀H₄₀N₂O₂461.31 460.2 64 OH (CH₂)₂-phenyl C₃₂H₄₄N₂O₂ 489.34 489.2 65 OH chexylC₃₀H₄₆N₂O₂ 467.36 467.4 66 OH (CH₂)₂-chexyl C₃₂H₅₀N₂O₂ 495.39 495.4 67OH NHCH₂-phenyl C₃₁H₄₃N₃O₂ 490.34 490.2 68 OH NHCH₂-chexyl C₃₁H₄₉N₃O₂496.38 496.4 69 OH CH₂OH C₂₅H₃₈N₂O₃ 415.29 415.2 70 OH (CH₂)₂C(O)NH₂C₂₇H₄₁N₃O₃ 456.32 456.2 71 OH (CH₂)₃N(CH₃)₂ C₂₉H₄₇N₃O₂ 470.37 470.4 72OH CH₃ C₂₅H₃₈N₂O₂ 399.29 399.2

TABLE 7

Ex Calc. Obs. No R¹ R³ Formula [M + H]⁺ [M + H]⁺ 73 OH (CH₂)₂-phenylC₃₂H₃₈N₂O₂ 483.29 483.2 74 OH chexyl C₃₀H₄₀N₂O₂ 461.31 461.2 75 OH(CH₂)₂-chexyl C₃₂H₄₄N₂O₂ 489.34 489.4 76 OH phenyl C₃₀H₃₄N₂O₂ 455.26455.2 77 OH NHCH₂-phenyl C₃₁H₃₇N₃O₂ 484.29 484.2 78 OH NHCH₂-chexylC₃₁H₄₃N₃O₂ 490.34 490.2 79 OH CH₂OC(O)CH₃ C₂₇H₃₄N₂O₄ 451.25 451.2 80 OH(CH₂)₂C(O)NH₂ C₂₇H₃₅N₃O₃ 450.27 450.2 81 OH (CH₂)₃N(CH₃)₂ C₂₉H₄₁N₃O₂464.32 464.2 82 OH CH₃ C₂₅H₃₂N₂O₂ 393.25 393.2

TABLE 8

Ex Calc. Obs. No R¹ R³ Formula [M + H]⁺ [M + H]⁺ 83 OH phenyl C₂₉H₃₈N₂O₂447.29 447.2 84 OH (CH₂)₂-phenyl C₃₁H₄₂N₂O₂ 475.32 475.2 85 OH chexylC₂₉H₄₄N₂O₂ 453.34 453.2 86 OH (CH₂)₂C(O)NH₂ C₂₆H₃₉N₃O₃ 442.30 442.2 87OH (CH₂)₃N(CH₃)₂ C₂₈H₄₅N₃O₂ 456.35 456.2 88 OH NHCH₂-phenyl C₃₀H₄₁N₃O₂476.32 476.2 89 OH (CH₂)₂-chexyl C₃₁H₄₈N₂O₂ 481.37 481.4 90 OHNHCH₂-chexyl C₃₀H₄₇N₃O₂ 482.37 482.2 91 OH CH₃ C₂₄H₃₆N₂O₂ 385.28 385.292 C(O)NH₂ CH₂OH C₂₅H₃₇N₃O₃ 428.28 428.4 93 C(O)NH₂ NHCH₂-phenylC₃₁H₄₂N₄O₂ 503.33 503.4 94 C(O)NH₂ NHCH₂-(4-F- C₃₁H₄₁FN₄O₂ 521.32 521.4phenyl)

TABLE 9

Ex Calc. Obs. No R¹ R³ Formula [M + H]⁺ [M + H]⁺ 95 C(O)NH₂ CH₂OHC₂₅H₃₁N₃O₃ 422.24 422.2 96 C(O)NH₂ NHC(CH₃)₂ C₂₇H₃₆N₄O₂ 449.28 449.4 97C(O)NH₂ (CH₂)₃C(O)OH C₂₈H₃₅N₃O₄ 478.26 478.4 98 C(O)NH₂ CH((S)—OH)CH₃C₂₆H₃₃N₃O₃ 436.25 436.4 99 C(O)NH₂ CH((S)—OH)CH₃ C₂₆H₃₃N₃O₃ 436.25 436.2100 C(O)NH₂ CH₂S(O)₂CH₃ C₂₆H₃₃N₃O₄S 484.22 484.2 * Denotes chiralcenter. Examples 98 and 99 have opposite stereochemistry at this center.

TABLE 10

Ex Calc. Obs. No R¹ R⁷ Formula [M + H]⁺ [M + H]⁺ 101 OH CH₃ C₂₃H₃₆N₂O₃S421.24 421.2 102 OH phenyl C₂₈H₃₈N₂O₃S 483.26 483.2 103 C(O)NH₂ CH₃C₂₄H₃₇N₃O₃S 448.26 448.4

TABLE 11

Ex Calc. Obs. No R¹ R⁷ Formula [M + H]⁺ [M + H]⁺ 104 C(O)NH₂ CH₃C₂₄H₃₁N₃O₃S 442.21 442.2 105 C(O)NH₂ CH₂S(O)₂CH₃ C₂₅H₃₃N₃O₅S₂ 520.19520.2

TABLE 12

Calc. Obs. Ex [M + [M + No R¹ R⁷ R^(a) n Formula H]⁺ H]⁺ 106 OH CH₃ H 1C₂₃H₃₆N₂O_(3S) 421.24 421.2 107 C(O)NH₂ CH₃ H 1 C₂₄H₃₇N₃O₃S 448.26 448.2108 C(O)NH₂ phenyl H 1 C₂₉H₃₉N₃O₃S 510.27 510.2 109 OH CH₃ H 2C₂₄H₃₈N₂O₃S 435.26 435.2 110 OH phenyl H 2 C₂₉H₄₀N₂O₃S 497.28 497.2 111C(O)NH₂ CH₃ CH₃ 1 C₂₅H₃₉N₃O₃S 462.27 462.4 112 C(O)NH₂ CH₂S(O)₂CH₃ H 1C₂₅H₃₉N₃O₅S₂ 526.23 526.2 113 C(O)NH₂ CH₂S(O)₂CH₃ CH₃ 1 C₂₆H₄₁N₃O₅S₂540.25 540.4

TABLE 13

Calc. Obs. Ex [M + [M + No R¹ R⁷ R^(a) n Formula H]⁺ H]⁺ 114 OH phenyl H1 C₂₈H₃₂N₂O₃S 477.21 477.2 115 C(O)NH₂ CH₃ H 1 C₂₃H₃₀N₂O₃S 415.20 415.2116 C(O)NH₂ phenyl H 1 C₂₄H₃₁N₃O₃S 442.21 442.2 117 OH CH₃ H 2C₂₄H₃₂N₂O₃S 429.21 429.2 118 OH phenyl H 2 C₂₉H₃₄N₂O₃S 491.23 491.2 119C(O)NH₂ CH₃ CH₃ 1 C₂₅H₃₃N₃O₃S 456.22 456.2 120 C(O)NH₂ CH₂S(O)₂CH₃ H 1C₂₅H₃₃N₃O₅S₂ 520.19 520.2 121 C(O)NH₂ CH₂S(O)₂CH₃ CH₃ 1 C₂₆H₃₅N₃O₅S₂534.20 534.2

TABLE 14

Ex Calc. Obs. No R Formula [M + H]⁺ [M + H]⁺ 122 CH₂-phenyl C₃₃H₃₈N₄O₃539.29 539.2 123 CH₂-indol-2-yl C₃₅H₃₉N₅O₃ 578.31 578.2 124 CH₃C₂₇H₃₄N₄O₃ 463.26 463.4 125 CH((R)—OH)CH₃ C₂₈H₃₆N₄O₄ 493.27 493.4 126CH₂-chexyl C₃₃H₄₄N₄O₃ 545.34 545.4 127 CH₂OH C₂₇H₃₄N₄O₄ 479.26 479.2 128CH₂-imidazol-2-yl C₃₀H₃₆N₆O₃ 529.29 529.2 129 CH₂C(O)NH₂ C₂₈H₃₅N₅O₄506.27 506.2 130 (CH₂)₂C(O)OH C₂₉H₃₆N₄O₅ 521.27 521.2 * Denotes a chiralcenter. Both the (R) and (S) diastereomers were prepared.

TABLE 15

Ex Calc. Obs. No R⁸ R^(f) Formula [M + H]⁺ [M + H]⁺ 131 CH₂C(O)NH₂ HC₂₆H₃₂N₄O₃ 449.25 449.2 132 CH₂C(O)N(CH₃)₂ H C₂₈H₃₆N₄O₃ 477.28 477.2 133(CH₂)₂OH H C₂₆H₃₃N₃O₃ 436.25 436.2 134 (CH₂)₂C(O)NH₂ H C₂₇H₃₄N₄O₃ 463.26463.2 135 4-S(O)₂NH₂-phenyl H C₃₀H₃₄N₄O₄S 547.23 547.2 136 (CH₂)₂N(CH₃)₂H C₂₈H₃₈N₄O₂ 463.30 463.2 137 (CH₂)₄N(CH₃)₂ H C₃₀H₄₂N₄O₂ 491.33 491.2138 (CH₂)₆NH₂ H C₃₀H₄₂N₄O₂ 491.33 491.2 139 (CH₂)₂OH CH₃ C₂₇H₃₅N₃O₃450.27 450.4

Assay 1: Radioligand Binding Assay on Human Mu, Human Delta and GuineaPig Kappa Opioid Receptors

a. Membrane Preparation

CHO-K1 (Chinese Hamster Ovary) cells stably transfected with human muopioid or with guinea pig kappa receptor cDNA were grown in mediumconsisting of Ham's-F12 media supplemented with 10% FBS, 100 units/mlpenicillin-100 μg/mL streptomycin and 800 μg/mL Geneticin in a 5% CO₂,humidified incubator @ 37° C. Receptor expression levels (B_(max)˜2.0and ˜0.414 pmol/mg protein, respectively) were determined using[³H]-Diprenorphine (specific activity ˜50-55 Ci/mmol) in a membraneradioligand binding assay.

Cells were grown to 80-95% confluency (<25 subculture passages). Forcell line passaging, the cell monolayer was incubated for 5 minutes atroom temperature and harvested by mechanical agitation in 10 mL of PBSsupplemented with 5 mM EDTA. Following resuspension, cells weretransferred to 40 mL fresh growth media for centrifugation for 5 minutesat 1000 rpm and resuspended in fresh growth medium at the appropriatesplit ratio.

For membrane preparation, cells were harvested by gentle mechanicalagitation with 5 mM EDTA in PBS followed by centrifugation (2500 g for 5minutes). The pellets were resuspended in Assay Buffer (50 mM4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acidN-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES)), pH7.4, and homogenized with a polytron disrupter on ice. The resultanthomogenates were centrifuged (1200 g for 5 minutes), the pelletsdiscarded and the supernatant centrifuged (40,000 g for 20 minutes). Thepellets were washed once by resuspension in Assay Buffer, followed by anadditional centrifugation (40,000 g for 20 minutes). The final pelletswere resuspended in Assay Buffer (equivalent 1 T-225 flask/1 mL assaybuffer). Protein concentration was determined using a Bio-Rad BradfordProtein Assay kit and membranes were stored in frozen aliquots at −80°C., until required.

Human delta opioid receptor (hDOP) membranes were purchased from PerkinElmer. The reported K_(d) and B_(max) for these membranes determined bysaturation analyses in a [³H]-Natrindole radioligand binding assays were0.14 nM (pK_(d)=9.85) and 2.2 pmol/mg protein, respectively. Proteinconcentration was determined using a Bio-Rad Bradford Protein Assay kit.Membranes were stored in frozen aliquots at −80° C., until required.

b. Radioligand Binding Assays

Radioligand binding assays were performed in an Axygen 1.1 mL deep well96-well polypropylene assay plate in a total assay volume of 200 μLcontaining the appropriate amount of membrane protein (˜3, ˜2 and ˜20 μgfor mu, delta and kappa, respectively) in Assay Buffer, supplementedwith 0.025% bovine serum albumin (BSA). Saturation binding studies fordetermination of K_(d) values of the radioligand were performed using[³H]-Diprenorphine at 8-12 different concentrations ranging from 0.001nM-5 nM. Displacement assays for determination of pKi values ofcompounds were performed with [³H]-Diprenorphine at 0.5, 1.2, and 0.7 nMfor mu, delta, and kappa, respectively, and eleven concentrations ofcompound ranging from 10 pM-100 μM.

Binding data were analyzed by nonlinear regression analysis with theGraphPad Prism Software package (GraphPad Software, Inc., San Diego,Calif.) using the 3-parameter model for one-site competition. The curveminimum was fixed to the value for nonspecific binding, as determined inthe presence of 10 μM naloxone. K_(i) values for test compounds werecalculated, in Prism, from the best fit IC₅₀ values, and the K_(d) valueof the radioligand, using the Cheng-Prusoff equation(K_(i)=IC₅₀/(1+([L]/K_(d))) where [L]=the concentration of[³H]-Diprenorphine. Results are expressed as the negative decadiclogarithm of the K_(i) values, pK_(i).

Test compounds having a higher pK_(i) value in these assays have ahigher binding affinity for the mu, delta, or kappa opioid receptor. Thecompounds of Examples 1-139 were tested in these assays. All of thecompounds had a pK_(i) value between about 8.5 and about 10.2 at thehuman mu opioid receptor. For example, the compounds of Examples 1through 6 had pK_(i) values of 10.2, 10.2, 9.9, 10.0, 9.1, and 10.2,respectively. Compounds of the invention also exhibited pK_(i) valuesbetween about 6.8 and about 10.3 human delta opioid receptor and betweenabout 8.4 and about 11.3 at the guinea pig kappa opioid receptor.

Assay 2: Agonist Mediated Activation of the Mu-Opioid Receptor inMembranes Prepared from CHO-K1 Cells Expressing the Human Mu-OpioidReceptor

In this assay, the potency and intrinsic activity values of testcompounds were determined by measuring the amount of bound GTP-Eupresent following receptor activation in membranes prepared from CHO-K1cells expressing the human mu opioid receptor.

a. Mu Opioid Receptor Membrane Preparation:

Human mu opioid receptor (hMOP) membranes were either prepared asdescribed above or were purchased from Perkin Elmer. The reported pK_(d)and B_(max) for the purchased membranes determined by saturationanalyses in a [³H]-Diprenorphine radioligand binding assays was 10.06and 2.4 pmol/mg protein, respectively. Protein concentration wasdetermined using a Bio-Rad Bradford Protein Assay kit. Membranes werestored in frozen aliquots at −80° C., until required. Lyophilized GTP-Euand GDP were diluted to 10 μM and 2 mM, respectively, in doubledistilled H₂O then mixed and permitted to sit at room temperature for 30minutes prior to transfer to individual aliquots samples for storage at−20° C.

b. Human mu GTP-Eu Nucleotide Exchange Assay

GTP-Eu nucleotide exchange assays were performed using the DELPHIAGTP-binding kit (Perkin/Elmer) in AcroWell 96 well filter platesaccording to the manufacturer's specifications. Membranes were preparedas described above, and prior to the start of the assay, aliquots werediluted to a concentration of 200 μg/mL in Assay Buffer (50 mM HEPES, pH7.4 at 25° C.), then homogenized for 10 seconds using a Polytronhomogenizer. Test compounds were received as 10 mM stock solutions inDMSO, diluted to 400 μM into Assay Buffer containing 0.1% BSA, andserial (1:5) dilutions then made to generate ten concentrations ofcompound ranging from 40 μM-80 μM—GDP and GTP-Eu were diluted to 4 μMand 40 nM, respectively, in Assay Buffer. The assay was performed in atotal volume of 100 μL containing 5 μg of membrane protein, testcompound ranging from 10 pM-20 μM), 1 μM GDP, and 10 nM GTP-Eu dilutedin 10 mM MgCl₂, 50 mM NaCl, and 0.0125% BSA, (final assayconcentrations). A DAMGO (Tyr-D-Ala-Gly-(methyl)Phe-Gly-ol)concentration-response curve (ranging from 12.8 pM-1 μM) was included onevery plate.

Assay plates were prepared immediately prior to assay following theaddition of 25 μL of Assay Buffer, 25 μL of test compound, and 25 μL GDPand GTP-Eu. The assay was initiated by the addition of 25 μL membraneprotein and allowed to incubate for 30 minutes. The assay plates werethen filtered with a Waters vacuum manifold connected to the housevacuum regulated to 10-12 in. Hg and washed with room temperature GTPWash Solution (2×300 mL). The bottoms of the plates were blotted toremove excess liquid. The plates were then immediately read to determinethe amount of bound GTP-Eu by measuring Time Resolved Fluorescence (TRF)on a Packard Fusion Plate ReaderVehicle: DMSO not to exceed 1% finalassay concentration.

The amount of bound GTP-Eu is proportional to the degree of activationof the mu opioid receptors by the test compound. The intrinsic activity(IA), expressed as a percentage, was determined as the ratio of theamount of bound GTP-Eu observed for activation by the test compound tothe amount observed for activation by DAMGO which is presumed to be afull agonist (IA=100). With the exception of the compounds of Examples76 and 104, the compounds of Examples 1 to 139 demonstrated intrinsicactivities in this assay of less than about 30. For example, thecompounds of Examples 1 through 6 had IA values of −9, 24, 3, −3, 2, and−7, respectively. Thus, the compounds of the present invention have beenshown to act as antagonists at the human mu opioid receptor.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. Additionally, all publications, patents, andpatent documents cited hereinabove are incorporated by reference hereinin full, as though individually incorporated by reference.

1. A method of treating a mammal having a medical condition amelioratedby treatment with a mu opioid receptor antagonist wherein the medicalcondition is opioid-induced bowel dysfunction or post-operative ileus,the method comprising administering to the mammal a therapeuticallyeffective amount of a pharmaceutical composition comprising apharmaceutically-acceptable carrier and a compound of formula (I):

wherein: R¹ is —OR^(a) or —C(O)NR^(b)R^(c); R² is selected from—NR^(a)C(O)R³, —NR^(a)C(O)NHR⁵, —NR^(a)S(O)₂R⁷, and —C(O)NR^(f)R⁸; R³ isselected from C₁₋₆ alkyl optionally substituted with one or twosubstituents selected from R⁴, C₅₋₆cycloalkyl, and phenyl optionallysubstituted with —S(O)₂NR^(b)R^(c); R⁴ is selected from —OR^(d),—C(O)NR^(b)R^(c), —NR^(b)R^(c), —C(O)OR^(d), —OC(O)R^(d), —S(O)₂R^(e),phenyl, and C₅₋₆cycloalkyl; R⁵ is C₁₋₆ alkyl optionally substituted withone or two substituents selected from C₅₋₆cycloalkyl and phenyloptionally substituted with halo, or —S(O)₂R⁶; R⁶ is C₁₋₆alkyl orphenyl; R⁷ is C₁₋₆ alkyl optionally substituted with —S(O)₂R^(e) orphenyl optionally substituted with C₁₋₃alkyl; R⁸ is C₁₋₆ alkyloptionally substituted with one or two substituents selected from R⁴,indolyl, and imidazolyl, or phenyl substituted with —S(O)₂NR^(b)R^(c);R^(a), R^(b), R^(c), R^(d), and R^(f) are each independently hydrogen orC₁₋₃alkyl; R^(e) is C₁₋₃alkyl; m is 0, 1, or 2; n is 0, 1, or 2; R⁹ andR¹⁰ are each hydrogen, or R⁹ and R¹⁰ taken together form —CH₂—, providedthat when R² is —C(O)NR^(f)R⁸, or when n is 0, R⁹ and R¹⁰ are eachhydrogen; and the dashed lines represent optional bonds; or apharmaceutically-acceptable salt thereof.
 2. The method of claim 1wherein R¹ is —OH or —C(O)NH₂.
 3. The method of claim 2 wherein: R³ isselected from C₁₋₄ alkyl optionally substituted with one substituentselected from —OH, —C(O)NH₂, —NH₂, —N(CH₃)₂, —C(O)OH, —OC(O)CH₃,—S(O)₂CH₃, and cyclohexyl, and phenyl optionally substituted with—S(O)₂NH₂; R⁵ is C₁₋₄ alkyl optionally substituted with one substituentselected from cyclohexyl, phenyl, and 4-fluorophenyl, or —S(O)₂-phenyl;R⁷ is C₁₋₄ alkyl optionally substituted with —S(O)₂CH₃, or phenyloptionally substituted with methyl; R⁸ is C₁₋₆ alkyl optionallysubstituted with one or two substituents selected from —OH, —C(O)NH₂,—NH₂, indolyl, and imidazolyl, or 4-S(O)₂NH₂-phenyl; R⁹ and R¹⁰ are eachhydrogen; and R^(a) is hydrogen or methyl.
 4. The method of claim 1wherein the optional bonds on the cyclic moiety bearing the substituentR⁹ are present.
 5. The method of claim 1 wherein the optional bonds onthe cyclic moiety bearing the substituent R⁹ are absent.
 6. The methodof claim 1 wherein m is 0 and n is
 1. 7. The method of claim 1 wherein mis 1 and n is
 0. 8. A method of reducing a gastrointestinal side effectassociated with use of an opioid agent in a mammal, the methodcomprising administering to the mammal an opioid agent and a compound offormula (I):

wherein: R¹ is —OR^(a) or —C(O)NR^(b)R^(c); R² is selected from—NR^(a)C(O)R³, —NR^(a)C(O)NHR⁵, —NR^(a)S(O)₂R⁷, and —C(O)NR^(f)R⁸; R³ isselected from C₁₋₆ alkyl optionally substituted with one or twosubstituents selected from R⁴, C₅₋₆cycloalkyl, and phenyl optionallysubstituted with —S(O)₂NR^(b)R^(c); R⁴ is selected from —OR^(d),—C(O)NR^(b)R^(c), —NR^(b)R^(c), —C(O)OR^(d), —OC(O)R^(d), —S(O)₂R^(e),phenyl, and C₅₋₆cycloalkyl; R⁵ is C₁₋₆ alkyl optionally substituted withone or two substituents selected from C₅₋₆cycloalkyl and phenyloptionally substituted with halo, or —S(O)₂R⁶; R⁶ is C₁₋₆alkyl orphenyl; R⁷ is C₁₋₆ alkyl optionally substituted with —S(O)₂R^(e) orphenyl optionally substituted with C₁₋₃alkyl; R⁸ is C₁₋₆ alkyloptionally substituted with one or two substituents selected from R⁴,indolyl, and imidazolyl, or phenyl substituted with —S(O)₂NR^(b)R^(c);R^(a), R^(b), R^(c), R^(d), and R^(f) are each independently hydrogen orC₁₋₃alkyl; R^(e) is C₁₋₃alkyl; m is 0, 1, or 2; n is 0, 1, or 2; R⁹ andR¹⁰ are each hydrogen, or R⁹ and R¹⁰ taken together form —CH₂—, providedthat when R² is —C(O)NR^(f)R⁸, or when n is 0, R⁹ and R¹⁰ are eachhydrogen; and the dashed lines represent optional bonds; or apharmaceutically-acceptable salt thereof.
 9. The method of claim 8wherein R¹ is —OH or —C(O)NH₂.
 10. The method of claim 9 wherein: R³ isselected from C₁₋₄ alkyl optionally substituted with one substituentselected from —OH, —C(O)NH₂, —NH₂, —N(CH₃)₂, —C(O)OH, —OC(O)CH₃,—S(O)₂CH₃, and cyclohexyl, and phenyl optionally substituted with—S(O)₂NH₂; R⁵ is C₁₋₄ alkyl optionally substituted with one substituentselected from cyclohexyl, phenyl, and 4-fluorophenyl, or —S(O)₂-phenyl;R⁷ is C₁₋₄ alkyl optionally substituted with —S(O)₂CH₃, or phenyloptionally substituted with methyl; R⁸ is C₁₋₆ alkyl optionallysubstituted with one or two substituents selected from —OH, —C(O)NH₂,—NH₂, indolyl, and imidazolyl, or 4-S(O)₂NH₂-phenyl; R⁹ and R¹⁰ are eachhydrogen; and R^(a) is hydrogen or methyl.
 11. The method of claim 8wherein the optional bonds on the cyclic moiety bearing the substituentR⁹ are present.
 12. The method of claim 8 wherein the optional bonds onthe cyclic moiety bearing the substituent R⁹ are absent.
 13. The methodof claim 8 wherein m is 0 and n is
 1. 14. The method of claim 8 whereinm is 1 and n is
 0. 15. A method of enhancing motility of thegastrointestinal tract in a mammal, the method comprising administeringto the mammal a pharmaceutical composition comprising apharmaceutically-acceptable carrier and a compound of formula (I):

wherein: R¹ is —OR^(a) or —C(O)NR^(b)R^(c); R² is selected from—NR^(a)C(O)R³, —NR^(a)C(O)NHR⁵, —NR^(a)S(O)₂R⁷, and —C(O)NR^(f)R⁸; R³ isselected from C₁₋₆ alkyl optionally substituted with one or twosubstituents selected from R⁴, C₅₋₆cycloalkyl, and phenyl optionallysubstituted with —S(O)₂NR^(b)R^(c); R⁴ is selected from —OR^(d),—C(O)NR^(b)R^(c), —NR^(b)R^(c), —C(O)OR^(d), —OC(O)R^(d), —S(O)₂R^(e),phenyl, and C₅₋₆cycloalkyl; R⁵ is C₁₋₆ alkyl optionally substituted withone or two substituents selected from C₅₋₆cycloalkyl and phenyloptionally substituted with halo, or —S(O)₂R⁶; R⁶ is C₁₋₆alkyl orphenyl; R⁷ is C₁₋₆ alkyl optionally substituted with —S(O)₂R^(e) orphenyl optionally substituted with C₁₋₃alkyl; R⁸ is C₁₋₆ alkyloptionally substituted with one or two substituents selected from R⁴,indolyl, and imidazolyl, or phenyl substituted with —S(O)₂NR^(b)R^(c);R^(a), R^(b), R^(c), R^(d), and R^(f) are each independently hydrogen orC₁₋₃alkyl; R^(e) is C₁₋₃alkyl; m is 0, 1, or 2; n is 0, 1, or 2; R⁹ andR¹⁰ are each hydrogen, or R⁹ and R¹⁰ taken together form —CH₂—, providedthat when R² is —C(O)NR^(f)R⁸, or when n is 0, R⁹ and R¹⁰ are eachhydrogen; and the dashed lines represent optional bonds; or apharmaceutically-acceptable salt thereof.
 16. The method of claim 15wherein R¹ is —OH or —C(O)NH₂.
 17. The method of claim 16 wherein: R³ isselected from C₁₋₄ alkyl optionally substituted with one substituentselected from —OH, —C(O)NH₂, —NH₂, —N(CH₃)₂, —C(O)OH, —OC(O)CH₃,—S(O)₂CH₃, and cyclohexyl, and phenyl optionally substituted with—S(O)₂NH₂; R⁵ is C₁₋₄ alkyl optionally substituted with one substituentselected from cyclohexyl, phenyl, and 4-fluorophenyl, or —S(O)₂-phenyl;R⁷ is C₁₋₄ alkyl optionally substituted with —S(O)₂CH₃, or phenyloptionally substituted with methyl; R⁸ is C₁₋₆ alkyl optionallysubstituted with one or two substituents selected from —OH, —C(O)NH₂,—NH₂, indolyl, and imidazolyl, or 4-S(O)₂NH₂-phenyl; R⁹ and R¹⁰ are eachhydrogen; and R^(a) is hydrogen or methyl.